Heterocyclic inhibitors of atr kinase

ABSTRACT

The present disclosure relates to heterocyclic compounds and methods which may be useful as inhibitors of ATR kinase for the treatment or prevention of cancer.

This application is a continuation of U.S. application Ser. No.16/507,851, filed Jul. 10, 2019, which is a continuation of U.S.application Ser. No. 16/035,310, filed Jul. 13, 2018, which claims thebenefit of priority of U.S. Provisional Application No. 62/531,951,filed Jul. 13, 2017, the disclosures of which are hereby incorporated byreference as if written herein in their entireties.

Disclosed herein are new heterocyclic compounds and compositions andtheir application as pharmaceuticals for the treatment of disease.Methods of inhibition of ATR kinase activity in a human or animalsubject are also provided for the treatment diseases such as cancer.

Ataxia-telangiectasia and Rad3-related kinase (ATR) is a member of thephosphatidylinositol 3-kinas-related protein kinase (PIKK) family, whichalso includes ataxia telangiectasia mutated (ATM) kinase, DNA-dependentprotein kinase (DNA-PK), suppressor of morphogenesis in genitalia-1(SMG-1), mammalian target of rapamycin (mTOR) andtransformation/transcription associated protein (TRAPP). ATR and ATM arekey regulators of the cellular DNA damage response (DDR) pathways, andare involved in maintaining the genome integrity in response toDNA-damage. Several distinct types of DNA lesions can occur as aconsequence of diverse damaging events, including errors in normalreplication processing, exposure to ionizing radiations (IR) andgenotoxic agents, and different mechanisms of DNA repair have evolved toresolve specific kinds of DNA damage.

ATM is activated mainly by double-stranded DNA breaks (DSB), which mayarise from collapsing of stalled replication forks or from exposure toIR. ATM has a key role in the activation of the G1/S checkpoint, whichprevents cells with DNA damage to enter the S-phase, and allows DNArepair prior to the start of DNA replication. The effect is mediatedprimarily through the phosphorylation of two of the main downstreamtargets of ATM, CHK2 kinase and the tumor suppressor p53.

In turn, ATR is activated mainly in response to single stranded DNAbreaks (SSB), that are found at stalled replication forks or are derivedfrom DNA end-resection following processing of DNA DSBs. Replicationprotein A (RPA) binds to the DNA single strands, the ATR-interactingprotein (ATRIP) binds then to the RPA-coated DNA strands and recruitsATR to the SSB damage site. Recruitment of additional protein componentsto the complex results in activation of ATR kinase, followed byphosphorylation and activation of its downstream effectors, includingCHK1 kinase. Activation of ATR results in slow replication originfiring, stabilization of the stalled replication forks which preventstheir collapse into DSBs, and restart of fork replication once thedamage is repaired. The ATR/CHK1 pathway is a major regulator of theG2/M checkpoint, which prevents the premature entry of cells intomitosis in the presence of incomplete DNA replication and/or DNA damage(reviewed in M. J. O'Connor, Molecular Cell, 2015, 60, November 19, p.547-560; A. M. Weber et al., Pharmacology and Therapeutics 2015, 149,124-138).

Because of the critical role of ATR in DDR, pharmacological inhibitionof ATR may be an effective cancer treatment in a number of specificsettings. Indeed, several cancers (e.g. oncogene-driven tumors) arecharacterized by higher levels of replication stress compared to normalcells, and blockade of ATR can increase their genomic instability andinduce substantial cell death (O. Gilad et al., Cancer Res. 70,9693-9702, 2010). Moreover, most cancers are characterized by loss orderegulation of one or more DDR pathways, resulting in increased genomicinstability and greater dependency on remaining DDR pathways forsurvival. For example, a cancer cell that has a defective G1 checkpointas a consequence of mutations in p53, will rely more on the G2/Mcheckpoints to allow DNA repair and cell survival. Inhibition of ATR, akey regulator of the G2/M checkpoints, can result in complete loss ofDNA damage checkpoints, ultimately leading to accumulation of DNA damageand mitotic catastrophe. Normal cells, with a functioning G1 checkpoint,would be less affected by pharmacological inhibition of ATR. Similarly,in cancer cells harboring ATM-deficiency, ATR inhibition results in asynthetic lethality dependency, leading to increased sensitivity andpreferential killing. Therefore, ATR inhibition could be used fortreatment of tumors with deficient ATM and/or p53 function (P. M.Reaper, M. R. Griffiths et al., Nature Chem. Bio. 7, 428-430, 2011)

Additional potential synthetic lethality interactions between ATR andother components of the DDR pathway have been reported, and might beexploited by treatment with ATR inhibitors, including treatment ofcancers characterized by loss/deficiency of XRCC1, ERCC1, MRE11 andother components if the MRN complex (reviewed in A. M. Weber et al.,Pharmacology and Therapeutics 2015, 149, 124-138). Recently, a syntheticlethality dependency has been reported for ATR inhibition in tumorsdeficient for ARID1-A, a member of the SWI/SNF chromatin-remodellingcomplex frequently mutated in human cancer (C. T. Williamson et al.,Nature Communications, 2016, 7, 13837).

ATR inhibition can be exploited for treatment of cancer also incombination with DNA-damaging therapeutic agents, such as radiotherapyand chemotherapy. Widely used chemotherapies include antimetabolites(e.g. gemcitabine), DNA crosslinking agents such as platinum salts,alkylating agents (e.g. temozolomide) and inhibitors of topoisomerase(e.g. camptothecin, topotecan, irinotecan). Administration of theseagents and/or ionizing radiation results in a variety of DNA lesionsthat ultimately bring the cancer cells towards mitotic catastrophe andcell death. In cancer cells treated with such agents, inhibition of ATRsignalling can prevent DNA damage repair, thus further reducing theoften already compromised abilities of cancer cells to respond to theinduced replication stress, and hence potentiating the effectiveness ofthe above treatments.

An additional opportunity to leverage ATR inhibition in combinationtherapy is together with other DDR agents, for example in combinationwith inhibitors of Poly ADP ribose polymerase (PARP). PARP inhibitorsprevent the repair of single strand DNA breaks, resulting into formationof DNA double strand breaks. In the context of cancers that aredeficient in the homologous recombination (HR) DNA repair pathway, suchas BRCA 1/2 mutant cancers, PARP inhibition has proven clinicallyefficacious. Recent reports highlight that targeting critical cell-cyclecheckpoints at the same time—for example by combining a PARP inhibitorwith an ATR inhibitor—results in increased sensitivity to PARPinhibition and in significant efficacy in several preclinical cancermodels, including PARP inhibitor resistant patient derived models. Thesefindings highlight the potential clinical applications of ATR inhibitionin combination with other DDR inhibitors, and the field is likely toexpand to several other combination opportunities beyond PARP inhibitors(H. Kim et al., Clinical Cancer Research, April 2017,DOI:10.1158/1078-0432.CCR-16-2273; A. Y. K. Lau et al., AACR NationalMeeting 2017, Abstract 2494/25, ATR inhibitor AZD6738 as monotherapy andin combination with olaparib or chemotherapy: defining pre-clinicaldose-schedules and efficacy modelling).

Thus, disclosed herein are methods for treating cancers using ATRinhibitors, in particular cancers characterized by elevated levels ofreplication stress, defective in cell cycle checkpoints, or harboringdefects in cellular DNA damage repair pathways, such as deficiency inthe ATM/p53 pathway or additional synthetic lethality dependencies withother DDR components. Also disclosed herein are methods using ATRinhibitors to treat cancers that are mutated/defective in ARID1A, or aremutated/defective in cellular pathways that are in a synthetic lethaldependency with the ATR pathway. Disclosed herein are also methods fortreatment of cancer using ATR inhibitors in combination with radiation,with DNA damaging chemotherapeutic agents, and with other DDRinhibitors, including PARP inhibitors.

Furthermore, inhibition of ATR offers an opportunity for treatment ofcertain cancers associated with the regulation of telomere length.Telomeres are nucleoprotein complexes comprising both hexanucleotide DNArepeat sequences and telomere-associated proteins, which act tostabilize the ends of chromosomes. In normal somatic cells, shorteningof the telomeres over time leads to senescence or apoptosis, and thisaction can act as an upper limit on cellular life span. In most advancedcancers, the enzyme telomerase is activated, whose role is to add arepeat sequence to the 3′ end of the DNA, thus reversing the telomereshortening process and increasing the cellular lifespan. Thus,activation of telomerase has been invoked in cancer cellimmortalization. A second, telomerase-independent mechanism formaintaining telomeres, termed Alternate Lengthening of Telomers (ALT),has been implicated in approximately 5% of all human cancers, and it isprevalent in specific kinds of cancer, including osteosarcoma andglioblastoma. ALT is enriched in mesenchymal-originating tumors, and isusually associated with decreased survival rates. Studies revealed thatATR kinase is functionally required for ALT, and that ALT cells are moresensitive to ATR inhibition (R. L. Flynn, K. E. Cox, Science 2015, 347(6219), 273-277).

There is a need for therapies having efficacy towards ALT-positivecancers. The ALT pathway is poorly understood, and cancers that featureALT are resistant to the action of telomerase inhibitors. Thus,described herein are methods for treating cancers, particularALT-positive types of cancers, using ATR inhibitors.

Disclosed herein are novel compounds and pharmaceutical compositions,certain of which have been found to inhibit ATR kinase, together withmethods of synthesizing and using the compounds, including methods forthe treatment of ATR kinase-mediated diseases in a patient byadministering the compounds.

Provided herein is Embodiment 1: a compound having structural Formula(I):

-   -   or a salt thereof, wherein:    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, any of which is optionally substituted with one or        more R⁵ groups, or R¹ and R², together with the sulfur to which        they are both attached, form a heterocycloalkyl ring which is        optionally substituted with one or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   R⁴ is chosen from C₅₋₁₀aryl and heteroaryl, either of which is        optionally substituted with one or more R⁶ groups;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl,        hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸, NR⁷C(O)NR⁸R⁹, C(O)R⁸,        C(O)OR⁸, and C(O)NR⁸R⁹;    -   each R⁶ is independently chosen from NR¹¹R¹², halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and heterocycloalkyl, any of which is        optionally substituted with halo, hydroxy, C₁₋₃alkyl,        C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸ and R⁹,        together with the atom to which they are both attached can form        a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and heterocycloalkyl, any of which is        optionally substituted with one or more groups chosen from halo,        hydroxy, and alkoxy; or any two of R¹⁰, R¹¹ and R¹², together        with the atom to which they are both attached, can form a 3-7        membered cycloalkyl or heterocycloalkyl ring.

Certain compounds disclosed herein may possess useful ATR kinaseinhibiting activity, and may be used in the treatment or prophylaxis ofa disease or condition in which ATR kinase plays an active role. Thus,in broad aspect, certain embodiments also provide pharmaceuticalcompositions comprising one or more compounds disclosed herein togetherwith a pharmaceutically acceptable carrier, as well as methods of makingand using the compounds and compositions. Certain embodiments providemethods for inhibiting ATR kinase. Other embodiments provide methods fortreating an ATR kinase-mediated disorder in a patient in need of suchtreatment, comprising administering to the patient in need thereof atherapeutically effective amount of a compound or composition accordingto the present disclosure. Also provided is the use of certain compoundsdisclosed herein for use in the manufacture of a medicament for thetreatment of a disease or condition ameliorated by the inhibition of ATRkinase.

In certain embodiments, R¹ and R² are independently chosen fromC₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,C₅₋₁₀aryl, and 5-10 membered heteroaryl, any of which is optionallysubstituted with one or more R⁵ groups, or R¹ and R², together with thesulfur to which they are both attached, form a heterocycloalkyl ringwhich is optionally substituted with one or more R⁵ groups.

In certain embodiments, R¹ and R² are independently chosen fromC₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,C₅₋₁₀aryl, and 5-10 membered heteroaryl, any of which is optionallysubstituted with one or more R⁵ groups, or R¹ and R², together with thesulfur to which they are both attached, form a heterocycloalkyl ringwhich is optionally substituted with one or more R⁵ groups.

In certain embodiments, R¹ and R² are independently chosen fromC₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,C₅₋₁₀aryl, and 5-10 membered heteroaryl, any of which is optionallysubstituted with one or more R⁵ groups, or R¹ and R², together with thesulfur to which they are both attached, form a 4, 5, 6, or 7-memberedheterocycloalkyl ring which is optionally substituted with one or moreR⁵ groups.

In certain embodiments, R⁴ is chosen from C₅₋₁₀ aryl andC₅₋₁₀heteroaryl, either of which is optionally substituted with one ormore R⁶ groups.

In certain embodiments, R⁴ is chosen from C₅₋₁₀ aryl and 5-10 memberedheteroaryl, either of which is optionally substituted with one or moreR⁶ groups.

In certain embodiments, R⁴ is chosen from

each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano, hydroxy,oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸, NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸,and C(O)NR⁸R⁹

In certain embodiments, each R⁵ is independently chosen from NR⁸R⁹,halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6membered heterocycloalkyl, hydroxyalkyl, OR⁸, NR⁷C(O)R⁸, NR⁷C(O)OR⁸,NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹.

In certain embodiments, each R⁵ is independently chosen from C(O)R⁸,C(O)OR⁸, and C(O)NR⁸R⁹.

In certain embodiments, each R⁵ is independently chosen from C(O)R⁸ andC(O)OR⁸.

In certain embodiments, each R⁶ is independently chosen from NR¹¹R¹²,halogen, cyano, hydroxy, oxo, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹,NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹².

In certain embodiments, each R⁶ is independently chosen from NR¹¹R¹²,halogen, cyano, hydroxy, and oxo.

In certain embodiments, each R⁶ is independently chosen from halogen andcyano.

In certain embodiments, each R⁷, R⁸ and R⁹ is independently chosen fromhydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,any of which is optionally substituted with halo, hydroxy, C₁₋₃alkyl,C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸ and R⁹, togetherwith the atom to which they are both attached can form a 3-7 memberedcycloalkyl or heterocycloalkyl ring.

In certain embodiments, each R¹⁰, R¹¹ and R¹² is independently chosenfrom hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 memberedheterocycloalkyl, any of which is optionally substituted with halo,hydroxy, C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸and R⁹, together with the atom to which they are both attached can forma 3-7 membered cycloalkyl or heterocycloalkyl ring.

The disclosure provides the further embodiments:

Embodiment 2: The compound of Embodiment 1, or salt thereof, wherein R³is chosen from methyl, fluoromethyl, difluoromethyl, andtrifluoromethyl.

Embodiment 3: The compound of Embodiment 1, or salt thereof, wherein R³is C₁₋₆alkyl.

Embodiment 4: The compound of Embodiment 3, or salt thereof, wherein R³is methyl.

Provided herein is Embodiment 5: a compound having structural Formula(II):

-   -   or a salt thereof, wherein:    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, C₅₋₁₀aryl,        and 5-10 membered heteroaryl, any of which is optionally        substituted with one or more R⁵ groups, or R¹ and R², together        with the sulfur to which they are both attached, form a 4, 5, 6,        or 7-membered heterocycloalkyl ring which is optionally        substituted with one or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   R⁴ is chosen from C₅₋₁₀aryl and 5-10 membered heteroaryl, either        of which is optionally substituted with one or more R⁶ groups;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹;    -   each R⁶ is independently chosen from NR¹¹R¹², halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹,        NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with halo, hydroxy,        C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸        and R⁹, together with the atom to which they are both attached        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with one or more groups        chosen from halo, hydroxy, and alkoxy; or any two of R¹⁰, R¹¹        and R¹², together with the atom to which they are both attached,        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

The disclosure provides the further embodiments:

Embodiment 6: The compound of Embodiment 5, or salt thereof, wherein R³is C₁₋₆alkyl.

Embodiment 7: The compound of Embodiment 6, or salt thereof, wherein R³is chosen from methyl, fluoromethyl, difluoromethyl, andtrifluoromethyl.

Embodiment 8: The compound of Embodiment 6, or salt thereof, wherein R³is methyl.

Embodiment 9: The compound of any of Embodiments 5-7, or salt thereof,wherein R⁴ is 5-10 membered heteroaryl and is optionally substitutedwith one or more R⁶ groups.

Embodiment 10: The compound of Embodiment 9, or salt thereof, wherein R⁴is chosen from indole, pyrrolopyridine, pyrazolopyridine,imidazopyridine, pyrrolopyrazine, pyrazolopyrazine, pyrrolopyrimidine,pyrazolopyrimidine, imidazolopyrimidine, pyrrolopyridazine,pyrazolopyridazine, and imidazolopyridazine, any of which is optionallysubstituted with one or more R⁶ groups.

Embodiment 11: The compound of Embodiment 9, wherein R⁴ is pyridine andis optionally substituted with one or more R⁶ groups.

Embodiment 12: The compound of Embodiment 11, wherein R⁴ isunsubstituted pyridine.

Embodiment 13: The compound of Embodiment 11, wherein R⁴ is pyridine andis substituted with one R⁶ group.

Embodiment 14: The compound of Embodiment 11, wherein R⁴ is pyridine andis substituted with two R⁶ groups.

Embodiment 15: The compound of Embodiment 10, or salt thereof, whereinR⁴ is selected from 1H-pyrrolo[2,3-b]pyridine,7H-pyrrolo[2,3-c]pyridazine, 7H-pyrrolo[2,3-d]-pyrimidine, and5H-pyrrolo[2,3-b]pyrazine, any of which is optionally substituted withone, two, or three R⁶ groups.

Embodiment 16: The compound of Embodiment 15, or salt thereof, whereinR⁴ is 1H-pyrrolo[2,3-b]pyridine and is optionally substituted with oneor two R⁶ groups.

Embodiment 17: The compound of any of Embodiments 5-16, or salt thereof,wherein wherein each R⁶ is independently selected from NR¹¹R¹², halogen,cyano, hydroxy, oxo, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹².

Embodiment 18: The compound of Embodiment 17, or salt thereof, whereineach R⁶ is independently selected from NR¹¹R¹², halogen, cyano, hydroxy,and oxo.

Embodiment 19: The compound of Embodiment 5-18, or salt thereof, whereinR⁴ is selected from

Embodiment 20: The compound of Embodiment 19, or salt thereof, wherein

-   -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆heterocycloalkyl, C₅₋₁₀aryl        and 5-10 membered heteroaryl, and are optionally substituted        with one or two R⁵ groups, or R¹ and R², together with the        sulfur to which they are both attached, form a 4, 5, 6, or        7-membered heterocycloalkyl ring which is optionally substituted        with one or two R⁵ groups;    -   each R⁵ is independently selected from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹.

Embodiment 21: The compound of Embodiment 20, or salt thereof, whereineach R⁵ is independently selected from alkyl, haloalkyl, C₃₋₆cycloalkyl,3-6 membered heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NRC(O)OR⁸,NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹.

Embodiment 22: The compound of Embodiment 21, or salt thereof, whereineach R⁵ is independently selected from C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹.

Embodiment 23: The compound of Embodiment 22, or salt thereof, whereinR¹ and R² are independently chosen from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, C₅₋₁₀aryl and 5-10membered heteroaryl, and are optionally substituted with one or two R⁵groups.

Embodiment 24: The compound of Embodiment 23, or salt thereof, whereinR¹ and R² are independently chosen from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl, and are optionallysubstituted with one or two R⁵ groups.

Embodiment 25: The compound of Embodiment 23, or salt thereof, whereinR¹ and R² are independently chosen from C₁₋₄alkyl and C₃₋₆cycloalkyl.

Embodiment 26: The compound of Embodiment 23, or salt thereof, whereinR¹ and R², together with the sulfur to which they are both attached,forms a heterocycloalkyl ring and is optionally substituted with one ortwo R⁵ groups.

Embodiment 27: The compound of Embodiment 10, or salt thereof, whereinR⁴ is chosen from 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl,1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, pyridin-3-yl,pyridin-4-yl, pyrimidin-4-yl, 1H-indol-1-yl, 1H-indol-4-yl,1H-indazol-1-yl, 1H-indazol-4-yl, 1H-benzo[d]imidazol-1-yl,1H-benzo[d]imidazol-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl,1H-pyrrolo[2,3-c]pyridin-4-yl, pyrazolo[1,5-a]pyridin-3-yl,imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl,1H-imidazo[4,5-c]pyridin-1-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl,1H-pyrazolo[3,4-b]pyridin-4-yl, 3H-imidazo[4,5-b]pyridin-7-yl, and1H-benzo[d][1,2,3]triazol-1-yl, any of which is optionally substitutedwith one or two R⁶ groups.

Embodiment 28: The compound of Embodiment 27, wherein R⁴ is chosen from1H-benzo[d]imidazol-1-yl,1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino, 1H-indol-4-yl,pyridin-4-yl, any of which is optionally substituted with one or two R⁶groups chosen from amino, fluoro, methyl, methoxy, difluoromethyl,trifluoromethyl, hydroxymethyl,1H-pyrrolo[2,3-c]pyridin-4-yl)pyrimidin-4-yl)imino.

Embodiment 29: The compound of Embodiment 27, or salt thereof, whereineach R⁶ is independently chosen from NR¹¹R¹², halogen, cyano, hydroxy,oxo, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹,C(O)OR¹¹, and C(O)NR¹¹R¹².

Embodiment 30: The compound of Embodiment 29, or salt thereof, whereineach R⁵ is independently chosen from C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹.

Embodiment 31: The compound of Embodiment 30, or salt thereof, whereinR¹ and R² are independently chosen from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, C₅₋₁₀aryl, and 5-10membered heteroaryl, any of which is optionally substituted with one ortwo R⁵ groups.

Embodiment 32: The compound of Embodiment 31, wherein R¹ and R² areindependently chosen from C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, and3-6 membered heterocycloalkyl, and are optionally substituted with oneor two R⁵ groups.

Embodiment 33: The compound of Embodiment 32, or salt thereof, whereinR¹ and R² are independently chosen from C₁₋₄alkyl, C₃₋₆cycloalkyl, and3-6 membered heterocycloalkyl.

Embodiment 34: The compound of Embodiment 32, or salt thereof, whereinR¹ and R² are independently chosen from C₁₋₄alkyl, C₃₋₆cycloalkyl, and3-6 membered heterocycloalkyl.

Embodiment 35: The compound of either of Embodiments 33 or 34, or saltthereof, wherein R⁴ is chosen from pyrrolo[2,3-b]pyridin-4-yl,1H-pyrrolo[2,3-b]pyridin-4-yl, pyrrolo[2,3-c]pyridin-4-yl,benzo[d]imidazol-1-yl.

Embodiment 36: The compound of Embodiment 36, or salt thereof, whereinR⁴ is chosen from 1H-benzo[d]imidazol-1-yl andpyrrolo[2,3-b]pyridin-4-yl, either of which is optionally substitutedwith one or two R⁶ groups.

Embodiment 37: The compound of Embodiment 36, or salt thereof, whereinR³ is methyl.

Embodiment 38: The compound of Embodiment 37, or salt thereof, whereinR¹ and R² are independently chosen from methyl, cyclopropyl, andoxetan-3-yl.

Embodiment 39: The compound of Embodiment 30, or salt thereof, whereinR¹ and R², together with the sulfur to which they are both attached,form a thiomorpholine ring which is optionally substituted with one ortwo R⁵ groups.

Embodiment 40: The compound of Embodiment 39, or salt thereof, whereinR¹ and R², together with the sulfur to which they are both attached,form a thiomorpholine ring which is substituted on the nitrogen eighthan R⁵ group chosen from chosen from C(O)R⁸ and C(O)OR⁸.

Provided herein is Embodiment 41: a compound having structural Formula(III):

-   -   or a salt thereof, wherein:    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, C₅₋₁₀aryl,        and 5-10 membered heteroaryl, any of which is optionally        substituted with one or more R⁵ groups, or R¹ and R², together        with the sulfur to which they are both attached, form a 4, 5, 6,        or 7-membered heterocycloalkyl ring which is optionally        substituted with one or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   R⁴ is chosen from C₅₋₁₀aryl and 5-10 membered heteroaryl, either        of which is optionally substituted with one or more R⁶ groups;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹;    -   each R⁶ is independently chosen from NR¹¹R¹², halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹,        NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with halo, hydroxy,        C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸        and R⁹, together with the atom to which they are both attached        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with one or more groups        chosen from halo, hydroxy and alkoxy; or any two of R¹⁰, R¹¹ and        R¹², together with the atom to which they are both attached, can        form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

The disclosure provides the further embodiments:

Embodiment 42: The compound of Embodiment 1, or salt thereof, wherein R⁴is 5-10 membered heteroaryl and is optionally substituted with one ormore R⁶ groups.

Embodiment 43: The compound of Embodiment 42, or salt thereof, whereinR⁴ is chosen from monocyclic 5-10 membered heteroaryl and bicyclic 5-10membered heteroaryl, either of which is optionally substituted with oneor more R⁶ groups.

Embodiment 44: The compound of Embodiment 43, or salt thereof, whereinR⁴ is chosen from pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl,indolyl, indazolyl, benzimidazolyl, benzotriazolyl, pyrrolopyridinyl,pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrazinyl,pyrazolopyrazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,imidazolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridazinyl, andimidazolopyridazinyl, any of which is optionally substituted with one ormore R⁶ groups.

Embodiment 45: The compound of Embodiment 44, or salt thereof, whereinR⁴ is chosen from pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl,indolyl, indazolyl, benzo[d]-imidazolyl, imidazo[1,2-a]pyridinyl,pyrazolo[1,5-a]pyridinyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[2,3-c]pyridinyl, benzo[d][1,2,3]triazolyl,pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl,imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl, any of which isoptionally substituted with one or more R⁶ groups.

Embodiment 46: The compound of Embodiment 44, or salt thereof, whereinR⁴ is chosen from 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl,1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, pyridin-3-yl,pyridin-4-yl, pyrimidin-4-yl, 1H-indol-1-yl, 1H-indol-4-yl,1H-indazol-1-yl, 1H-indazol-4-yl, 1H-benzo[d]imidazol-1-yl,1H-benzo[d]imidazol-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl,1H-pyrrolo[2,3-c]pyridin-4-yl, pyrazolo[1,5-a]pyridin-3-yl,imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl,1H-imidazo[4,5-c]pyridin-1-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl,1H-pyrazolo[3,4-b]pyridin-4-yl, 3H-imidazo[4,5-b]pyridin-7-yl, and1H-benzo[d][1,2,3]triazol-1-yl, any of which is optionally substitutedwith one or two R⁶ groups.

Embodiment 47: The compound of Embodiment 45, or salt thereof, whereinR⁴ is chosen from imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridazinyl,and imidazo[4,5-b]pyrazinyl, any of which is optionally substituted withone, two, or three R⁶ groups.

Embodiment 48: The compound of Embodiment 47, or salt thereof, whereinR⁴ is chosen from pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridazinyl,pyrrolo[2,3-d]pyrimidinyl, and pyrrolo[2,3-b]pyrazine, any of which isoptionally substituted with one, two, or three R⁶ groups.

Embodiment 49: The compound of Embodiment 48, or salt thereof, whereinR⁴ is pyrrolo[2,3-b]pyridinyl and is optionally substituted with one ortwo R⁶ groups.

Provided herein is Embodiment 50: a compound having structural Formula(IV):

-   -   or a salt thereof, wherein:    -   X is chosen from N and CR^(6c);    -   Y is chosen from N and CR^(6d);    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, C₅₋₁₀aryl,        and 5-10 membered heteroaryl, any of which is optionally        substituted with one or more R⁵ groups, or R¹ and R², together        with the sulfur to which they are both attached, form a 4, 5, 6,        or 7-membered heterocycloalkyl ring which is optionally        substituted with one or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹;    -   R^(6a) and R^(6b) are independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²,    -   or R^(6a) and R^(6b), together with the intervening atoms,        combine to form a heteroaryl ring, which is optionally        substituted with one or more R⁶ groups;    -   each R^(6c) and R^(6d) is independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²;    -   R⁶ is chosen from NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl,        haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with halo, hydroxy,        C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸        and R⁹, together with the atom to which they are both attached        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with one or more groups        chosen from halo, hydroxy and alkoxy; or any two of R¹⁰, R¹¹ and        R¹², together with the atom to which they are both attached, can        form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

Provided herein is Embodiment 51: a compound having structural Formula(IVa):

-   -   or a salt thereof, wherein:    -   X is chosen from N and CR⁶;    -   Y is chosen from N and CR^(6d);    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, C₅₋₁₀aryl,        and 5-10 membered heteroaryl, any of which is optionally        substituted with one or more R⁵ groups, or R¹ and R², together        with the sulfur to which they are both attached, form a 4, 5, 6,        or 7-membered heterocycloalkyl ring which is optionally        substituted with one or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹;    -   R^(6a) and R^(6b) are independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹² or R^(6a) and R^(6b), together with the intervening        atoms, combine to form a heteroaryl ring, which is optionally        substituted with one or more R⁶ groups;    -   each R^(6c) and R^(6d) is independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²;    -   R⁶ is chosen from NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl,        haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with halo, hydroxy,        C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸        and R⁹, together with the atom to which they are both attached        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with one or more groups        chosen from halo, hydroxy and alkoxy; or any two of R¹⁰, R¹¹ and        R¹², together with the atom to which they are both attached, can        form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

The disclosure provides the further embodiments:

Embodiment 52: The compound of either one of Embodiments 50 or 51, orsalt thereof, wherein R₃ is C₁₋₆alkyl.

Embodiment 53: The compound of either one of Embodiments 50 or 51, orsalt thereof, wherein wherein R₃ is chosen from methyl, fluoromethyl,difluoromethyl, and trifluoromethyl.

Embodiment 54: The compound of either one of Embodiments 50 or 51, orsalt thereof, wherein R₃ is methyl.

Embodiment 55: The compound of any one of Embodiments 50-54, or saltthereof, wherein R^(6a) and R^(6b), together with the intervening atoms,combine to form a five-membered heteroaryl ring chosen from pyrrole,pyrazole, and imidazole, any of which is optionally substituted with oneor more R⁶ groups.

Embodiment 56: The compound of any one of Embodiments 50-55, or saltthereof, wherein R⁶ is chosen from alkyl, haloalkyl, and cycloalkyl.

Embodiment 57: The compound of any one of Embodiments 50-56, or saltthereof, wherein:

X is CR^(6c); and

Y is N.

Embodiment 58: The compound of any one of Embodiments 50-54 or saltthereof, wherein R^(6a) and R^(6b) are independently chosen from H,NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl, OR¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹².

Embodiment 59: The compound of Embodiment 58, or salt thereof, whereinR^(6b) is H.

Embodiment 60: The compound of either one of Embodiments 58 or 59, orsalt thereof, wherein R^(6a) is chosen from H, alkyl, haloalkyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, and OR¹¹.

Embodiment 61: The compound of any one of Embodiments 58-60, or saltthereof, wherein

X is CR^(6c); and

Y is N.

Embodiment 62: The compound of any one of Embodiments 58-61, or saltthereof, wherein R⁶, is NH₂.

Embodiment 63: The compound of any one of Embodiments 58-62, or saltthereof, wherein R^(6a) is chosen from H and OR¹¹.

Embodiment 64: The compound of any one of Embodiments 58-63, or saltthereof, wherein R¹¹ is C₁₋₄alkyl.

Embodiment 65: The compound of any one of Embodiments 58-64, or saltthereof, wherein wherein R¹ and R² are independently chosen fromcyclopropyl, oxetan-3-yl, and methyl.

Embodiment 66: The compound of any one of Embodiments 58-65, or saltthereof, wherein at least one of R¹ and R² is methyl.

Embodiment 67: The compound of any one of Embodiments 58-66, or saltthereof, wherein one of R¹ and R² is methyl.

Embodiment 68: The compound of Embodiment 66, or salt thereof, whereinR¹ and R² are methyl.

Embodiment 69: The compound of Embodiment 66, or salt thereof, whereinR¹ is methyl and R² is cyclopropyl.

Embodiment 70: The compound Embodiment 66, or salt thereof, wherein R¹is cyclopropyl and R² is methyl.

Provided herein is Embodiment 71: a compound having structural Formula(V):

-   -   or a salt thereof, wherein:    -   X is chosen from N and CR⁶;    -   Y is chosen from N and CR^(6d);    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, C₅₋₁₀aryl,        and heteroaryl, any of which is optionally substituted with one        or more R⁵ groups, or R¹ and R², together with the sulfur to        which they are both attached, form a 4, 5, 6, or 7-membered        heterocycloalkyl ring which is optionally substituted with one        or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹;    -   R^(6a) and R^(6b) are independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹² or R^(6a) and R^(6b), together with the intervening        atoms, combine to form a heteroaryl ring, which is optionally        substituted with one or more R⁶ groups;    -   each R^(6c) and R^(6d) is independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²;    -   R⁶ is chosen from NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl,        haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with halo, hydroxy,        C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸        and R⁹, together with the atom to which they are both attached        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with one or more groups        chosen from halo, hydroxy and alkoxy; or any two of R¹⁰, R¹¹ and        R¹², together with the atom to which they are both attached, can        form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

Provided herein is Embodiment 72: a compound having structural Formula(Va):

-   -   or a salt thereof, wherein:    -   X is chosen from N and CR⁶;    -   Y is chosen from N and CR^(6d);    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, C₅₋₁₀aryl,        and 5-10 membered heteroaryl, any of which is optionally        substituted with one or more R⁵ groups, or R¹ and R², together        with the sulfur to which they are both attached, form a 4, 5, 6,        or 7-membered heterocycloalkyl ring which is optionally        substituted with one or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹;    -   R^(6a) and R^(6b) are independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹² or R^(6a) and R^(6b), together with the intervening        atoms, combine to form a heteroaryl ring, which is optionally        substituted with one or more R⁶ groups;    -   each R^(6c) and R^(6d) is independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²;    -   R⁶ is chosen from NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl,        haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with halo, hydroxy,        C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸        and R⁹, together with the atom to which they are both attached        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with one or more groups        chosen from halo, hydroxy and alkoxy; or any two of R¹⁰, R¹¹ and        R¹², together with the atom to which they are both attached, can        form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

The disclosure provides the further embodiments:

Embodiment 73: The compound either one of Embodiments 71 or 72, or saltthereof, wherein R^(6a) and R^(6b), together with the intervening atoms,combine to form a pyridyl ring.

Embodiment 74: The compound of any one of Embodiments 71-73, or saltthereof, wherein:

-   -   R^(6a) and R^(6b) are independently chosen from H, alkyl,        haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, and        hydroxyalkyl; and    -   each R^(6c) and R^(6d) is independently chosen from H, alkyl,        haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, and        hydroxyalkyl.

Embodiment 75: The compound of Embodiment 71, wherein the compound is

or a salt thereof.

Provided herein is Embodiment 76: a compound having structural Formula(VI):

-   -   or a salt thereof, wherein:    -   X is chosen from N and CR⁶;    -   Y is chosen from N and CR^(6d);    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, C₅₋₁₀aryl,        and 5-10 membered heteroaryl, any of which is optionally        substituted with one or more R⁵ groups, or R¹ and R², together        with the sulfur to which they are both attached, form a 4, 5, 6,        or 7-membered heterocycloalkyl ring which is optionally        substituted with one or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹;    -   R^(6a) and R^(6b) are independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹², or R^(6a) and R^(6b), together with the intervening        atoms, combine to form a heteroaryl ring, which is optionally        substituted with one or more R⁶ groups;    -   each R^(6c) and R^(6d) is independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²;    -   R⁶ is chosen from NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl,        haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with halo, hydroxy,        C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸        and R⁹, together with the atom to which they are both attached        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with one or more groups        chosen from halo, hydroxy and alkoxy; or any two of R¹⁰, R¹¹ and        R¹², together with the atom to which they are both attached, can        form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

Provided herein is Embodiment 77: a compound having structural Formula(VIa):

-   -   or a salt thereof, wherein:    -   X is chosen from N and CR⁶;    -   Y is chosen from N and CR^(6d);    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, C₅₋₁₀aryl,        and 5-10 membered heteroaryl, any of which is optionally        substituted with one or more R⁵ groups, or R¹ and R², together        with the sulfur to which they are both attached, form a 4, 5, 6,        or 7-membered heterocycloalkyl ring which is optionally        substituted with one or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹;    -   R^(6a) and R^(6b) are independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²,    -   or R^(6a) and R^(6b), together with the intervening atoms,        combine to form a heteroaryl ring, which is optionally        substituted with one or more R⁶ groups;    -   each R^(6c) and R^(6d) is independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²;    -   R⁶ is chosen from NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl,        haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with halo, hydroxy,        C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸        and R⁹, together with the atom to which they are both attached        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with one or more groups        chosen from halo, hydroxy and alkoxy; or any two of R¹⁰, R¹¹ and        R¹², together with the atom to which they are both attached, can        form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

The disclosure provides the further embodiments:

Embodiment 78: The compound of either one Embodiment 76 or 77, or saltthereof, wherein R^(6a) and R^(6b), together with the intervening atoms,combine to form a pyridyl ring.

Embodiment 79: The compound of any one of Embodiments 76-78, or saltthereof, wherein each R^(6c) and R^(6d) is independently chosen from H,alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, andhydroxyalkyl.

Embodiment 80: The compound of Embodiment 76, wherein the compound ischosen from

or a salt thereof.

Provided herein is Embodiment 81: a compound having structural Formula(VII):

-   -   or a salt thereof, wherein:    -   X is chosen from N and CR^(6c);    -   Y is chosen from N and CR^(6d);    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, C₅₋₁₀aryl,        and 5-10 membered heteroaryl, any of which is optionally        substituted with one or more R⁵ groups, or R¹ and R², together        with the sulfur to which they are both attached, form a 4, 5, 6,        or 7-membered heterocycloalkyl ring which is optionally        substituted with one or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹;    -   R^(6a) and R^(6b) are independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹², or R^(6a) and R^(6b), together with the intervening        atoms, combine to form an aryl or heteroaryl ring, which is        optionally substituted with one or more R⁶ groups;    -   each R^(6c) and R^(6d) is independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²;    -   R⁶ is chosen from NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl,        haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with halo, hydroxy,        C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸        and R⁹, together with the atom to which they are both attached        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with one or more groups        chosen from halo, hydroxy and alkoxy; or any two of R¹⁰, R¹¹ and        R¹², together with the atom to which they are both attached, can        form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

Provided herein is Embodiment 82: a compound having structural Formula(VIIa):

-   -   or a salt thereof, wherein:    -   X is chosen from N and CR⁶;    -   Y is chosen from N and CR^(6d);    -   R¹ and R² are independently chosen from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, C₅₋₁₀aryl,        and 5-10 membered heteroaryl, any of which is optionally        substituted with one or more R⁵ groups, or R¹ and R², together        with the sulfur to which they are both attached, form a 4, 5, 6,        or 7-membered heterocycloalkyl ring which is optionally        substituted with one or more R⁵ groups;    -   R³ is chosen from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   each R⁵ is independently chosen from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered        heterocycloalkyl, hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸,        NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹;    -   R^(6a) and R^(6b) are independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²,    -   or R^(6a) and R^(6b), together with the intervening atoms,        combine to form an aryl or heteroaryl ring, which is optionally        substituted with one or more R⁶ groups;    -   each R^(6c) and R^(6d) is independently chosen from H, NR¹¹R¹²,        halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,        3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and        C(O)NR¹¹R¹²;    -   R⁶ is chosen from NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl,        haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with halo, hydroxy,        C₁₋₃alkyl, C₁₋₃haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸        and R⁹, together with the atom to which they are both attached        can form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently chosen from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl,        any of which is optionally substituted with one or more groups        chosen from halo, hydroxy and alkoxy; or any two of R¹⁰, R¹¹ and        R¹², together with the atom to which they are both attached, can        form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

The disclosure provides the further embodiments:

Embodiment 83: The compound of either one of Embodiments 81 or 82, orsalt thereof, wherein R^(6a) and R^(6b), together with the interveningatoms, combine to form a phenyl ring, which is optionally substitutedwith one or two R⁶ groups.

Embodiment 84: The compound of any one of Embodiments 81-83, or saltthereof, wherein X is CR^(6′) and Y is N.

Embodiment 85: The compound of any one of Embodiments 81-84, or saltthereof, wherein R^(6c) is chosen from H, alkyl, haloalkyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, and hydroxyalkyl.

Embodiment 86: The compound of Embodiment 85, or salt thereof, whereinR^(6c) is chosen from H and alkyl.

Embodiment 87: The compound of Embodiment 86, or salt thereof, whereinR^(6c) is chosen from H and methyl.

Embodiment 88: The compound of Embodiment 86, or salt thereof, whereinR^(6c) is methyl.

Embodiment 89: The compound of any one of Embodiments 81-88, or saltthereof, wherein R¹ and R² are independently chosen from C₁₋₄alkyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl.

Embodiment 90: The compound of any one of Embodiments 81-88, or saltthereof, wherein R¹ and R² are independently chosen from C₁₋₄alkyl,C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl.

Embodiment 91: The compound of Embodiment 89, or salt thereof, whereinat least one of R¹ and R² is methyl.

Embodiment 92: The compound of Embodiment 89, or salt thereof, whereinexactly one of R¹ and R² is chosen from cyclopropyl and oxetan-3-yl.

Embodiment 93: The compound of Embodiment 91, or salt thereof, whereinexactly one of R¹ and R² is cyclopropyl.

Embodiment 94: The compound of Embodiment 91, or salt thereof, whereinR¹ and R² are methyl.

Embodiment 95: The compound of any one of Embodiments 81-93, or saltthereof, wherein R¹ and R² are are independently chosen from C₁₋₄alkyland C₃₋₆cycloalkyl.

Embodiment 96: The compound of Embodiment 81, or salt thereof, whereinthe compound is chosen from:

or a salt thereof.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R^(6a) and R^(6b),together with the intervening atoms, combine to form a heteroaryl ring,which is optionally substituted with one or more R⁶ groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R^(6a) and R^(6b),together with the intervening atoms, combine to form a five-memberedheteroaryl ring, which is optionally substituted with one or two R⁶groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R^(6a) and R^(6b),together with the intervening atoms, combine to form a five-memberedheteroaryl ring chosen from pyrrole, pyrazole, and imidazole, any ofwhich is optionally substituted with one or two R⁶ groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R^(6a) and R^(6b),together with the intervening atoms, combine to form a six-memberedheteroaryl ring, which is optionally substituted with one or two R⁶groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R^(6a) and R^(6b),together with the intervening atoms, combine to form a pyridine ring,which is optionally substituted with one or two R⁶ groups.

In certain embodiments of compounds having formula chosen from (IV) and(IVa), R^(6a) and R^(6b), together with the intervening atoms, combineto form an aryl ring, which is optionally substituted with one or moreR⁶ groups.

In certain embodiments of compounds having formula chosen from (IV) and(IVa), R^(6a) and R^(6b), together with the intervening atoms, combineto form a phenyl ring, which is optionally substituted with one or twoR⁶ groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R⁶ is chosen from halogen,cyano, alkyl, haloalkyl, and cycloalkyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), X is N and Y is CR⁶.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), X is CR^(6′) and Y is N.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), X and Y are both CR⁶.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R^(6a) and R^(6b) areindependently chosen from H, NR¹¹R¹², halogen, cyano, hydroxy, oxo,alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl,hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹,C(O)OR¹¹, and C(O)NR¹¹R¹²;

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R^(6a) and R^(6b) areindependently chosen from H, NR¹¹R¹², halogen, alkyl, haloalkyl,C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R^(6b) is H.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R^(6a) is H.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), each R^(6c) and R^(6d) isindependently chosen from H, NH₂, halogen, cyano, alkyl, OR¹¹, andC(O)NR¹¹R¹².

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), at most one R⁶, is not H

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R^(6c) is H.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R¹ and R² areindependently chosen from C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, 3-6membered heterocycloalkyl, C₅₋₁₀aryl, and 5-10 membered heteroaryl, anyof which is optionally substituted with one or more R⁵ groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R¹ and R² areindependently chosen from C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, and3-6 membered heterocycloalkyl, any of which is optionally substitutedwith one or more R⁵ groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R¹ and R² areindependently chosen from C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 memberedheterocycloalkyl, any of which is optionally substituted with one or twoR⁵ groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), at least one of R¹ and R²is C₁₋₄alkyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), least one of R¹ and R² ismethyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R¹ and R² areindependently chosen from C₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆cycloalkyl, and3-6 membered heterocycloalkyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), at least one of R¹ and R²is C₁₋₄alkyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), at least one of R¹ and R²is methyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), one of R¹ and R² is chosenfrom C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), one of R¹ and R² is chosenfrom cyclopropyl and oxetan-3-yl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R¹ and R² are methyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R¹ and R², together withthe sulfur to which they are both attached, form a 4, 5, 6, or7-membered heterocycloalkyl ring which is optionally substituted withone or more R⁵ groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R¹ and R², together withthe sulfur to which they are both attached, form a 5-7 memberedheterocycloalkyl ring which is optionally substituted with one or two R⁵groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R¹ and R², together withthe sulfur to which they are both attached, form a 5-7 memberedheterocycloalkyl ring chosen from thiane and thiomorpholine, either ofwhich is optionally substituted with one or two R⁵ groups.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R¹ and R², together withthe sulfur to which they are both attached, form a 4, 5, 6, or7-membered heterocycloalkyl ring.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), each R⁵ is independentlychosen from halogen, cyano, hydroxy, OR⁸, C(O)R⁸, C(O)OR⁸, andC(O)NR⁸R⁹.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), each R⁵ is independentlychosen from C(O)R⁸ and C(O)OR⁸.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), each R⁸ is independentlychosen from hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 memberedheterocycloalkyl, any of which is optionally substituted with halo,hydroxy, and C₁₋₃alkoxy.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R³ is H.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R³ is chosen fromC₁₋₆alkyl and C₁₋₆haloalkyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R³ is chosen fromC₁₋₆alkyl and C₁₋₆fluoroalkyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R³ is chosen from methyl,fluoromethyl, difluoromethyl, and trifluoromethyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R³ is C₁₋₆alkyl.

In certain embodiments of compounds having formula chosen from (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), R³ is methyl.

In certain embodiments of compounds having formula chosen from (I),(II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa),any alkoxy recited is a C₁₋₃alkoxy.

In certain embodiments, the compound is chosen from:

or a salt of any of the foregoing.

In certain embodiments, the compound is chosen from:

or a salt of any of the foregoing.

The disclosure provides the further embodiments:

Embodiment 97: The compound of any one of Embodiments 50, 51, 71, 72,76, 77, 81, or 82, or salt thereof, wherein R^(6a) and R^(6b), togetherwith the intervening atoms, combine to form a heteroaryl ring, which isoptionally substituted with one or more R⁶ groups.

Embodiment 98: The compound of Embodiment 97, or salt thereof, whereinR^(6a) and R^(6b), together with the intervening atoms, combine to forma five-membered heteroaryl ring, which is optionally substituted withone or two R⁶ groups.

Embodiment 99: The compound of Embodiment 98, or salt thereof, whereinR^(6a) and R^(6b), together with the intervening atoms, combine to forma five-membered heteroaryl ring chosen from pyrrole, pyrazole, andimidazole, any of which is optionally substituted with one or two R⁶groups.

Embodiment 100: The compound of Embodiment 97, or salt thereof, whereinR^(6a) and R^(6b), together with the intervening atoms, combine to forma six-membered heteroaryl ring, which is optionally substituted with oneor two R⁶ groups.

Embodiment 101: The compound of Embodiment 100, or salt thereof, whereinR^(6a) and R^(6b), together with the intervening atoms, combine to forma pyridine ring, which is optionally substituted with one or two R⁶groups.

Embodiment 102: The compound of Embodiment 81, or salt thereof, whereinR^(6a) and R^(6b), together with the intervening atoms, combine to forman aryl ring, which is optionally substituted with one or more R⁶groups.

Embodiment 103: The compound of Embodiment 102, or salt thereof, whereinR^(6a) and R^(6b), together with the intervening atoms, combine to forma phenyl ring, which is optionally substituted with one or two R⁶groups.

Embodiment 104: The compound of any one of Embodiments 97-103, or saltthereof, wherein R⁶ is chosen from halogen, cyano, alkyl, haloalkyl, andcycloalkyl.

Embodiment 105: The compound of any one of Embodiments 50-104, or saltthereof, wherein X is N and Y is CR⁶.

Embodiment 106: The compound of any one of Embodiments 50-104, or saltthereof, wherein X is CR^(6c) and Y is N.

Embodiment 107: The compound of any one of Embodiments 50-104, or saltthereof, wherein X and Y are both CR⁶.

Embodiment 108: The compound of any one of Embodiments 50-81, or saltthereof, wherein R^(6a) and R^(6b) are independently chosen from H,NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl,3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹².

Embodiment 109: The compound of Embodiment 108, wherein R^(6a) andR^(6b) are independently chosen from H, NR¹¹R¹², halogen, alkyl,haloalkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl.

Embodiment 110: The compound of either one of Embodiments 108 or 109, orsalt thereof, wherein R^(6b) is H.

Embodiment 111: The compound of any one of Embodiments 108, 109, or 110,or salt thereof, wherein R^(6a) is H.

Embodiment 112: The compound of any one of Embodiments 50-111, or saltthereof, wherein each R^(6c) and R^(6d) is independently chosen from H,NH₂, halogen, cyano, alkyl, OR¹¹, and C(O)NR¹¹R¹².

Embodiment 113: The compound of Embodiment 112, or salt thereof, whereinat most one R⁶, is not H.

Embodiment 114: The compound of Embodiment 112, or salt thereof, whereinR⁶, is H.

Embodiment 115: The compound of any one of Embodiments 1-114, or saltthereof, wherein R¹ and R² are independently chosen from C₁₋₄alkyl,C₁₋₄haloalkyl, C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, C₅₋₁₀aryl,and 5-10 membered heteroaryl, any of which is optionally substitutedwith one or more R⁵ groups.

Embodiment 116: The compound of Embodiment 115, or salt thereof, whereinR¹ and R² are independently chosen from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl, any of which isoptionally substituted with one or more R⁵ groups.

Embodiment 117: The compound of Embodiment 116, or salt thereof, whereinR¹ and R² are independently chosen from C₁₋₄alkyl, C₃₋₆cycloalkyl, and3-6 membered heterocycloalkyl, any of which is optionally substitutedwith one or two R⁵ groups.

Embodiment 118: The compound of any one of Embodiment 115-117, or saltthereof, wherein at least one of R¹ and R² is C₁₋₄alkyl.

Embodiment 119: The compound of Embodiment 118, or salt thereof, whereinat least one of R¹ and R² is methyl.

Embodiment 120: The compound of Embodiment 116, or salt thereof, whereinR¹ and R² are independently chosen from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl.

Embodiment 121: The compound of Embodiment 120, or salt thereof, whereinat least one of R¹ and R² is C₁₋₄alkyl.

Embodiment 122: The compound of Embodiment 121, or salt thereof, whereinat least one of R¹ and R² is methyl.

Embodiment 123: The compound of either one of Embodiments 121 or 122, orsalt thereof, wherein one of R¹ and R² is chosen from C₃₋₆cycloalkyl,and 3-6 membered heterocycloalkyl.

Embodiment 124: The compound of Embodiment 123, or salt thereof, whereinone of R¹ and R² is chosen from cyclopropyl and oxetan-3-yl.

Embodiment 125: The compound of Embodiment 122, or salt thereof, whereinR¹ and R² are methyl.

Embodiment 126: The compound of any one of Embodiments 1-111, or saltthereof, wherein R¹ and R², together with the sulfur to which they areboth attached, form a 4, 5, 6, or 7-membered heterocycloalkyl ring whichis optionally substituted with one or more R⁵ groups.

Embodiment 127: The compound of Embodiment 126, or salt thereof, whereinR¹ and R², together with the sulfur to which they are both attached,form a 5-7 membered heterocycloalkyl ring which is optionallysubstituted with one or two R⁵ groups.

Embodiment 128: The compound of Embodiment 127, or salt thereof, whereinR¹ and R², together with the sulfur to which they are both attached,form a 5-7 membered heterocycloalkyl ring chosen from thiane andthiomorpholine, either of which is optionally substituted with one ortwo R⁵ groups.

Embodiment 129: The compound of Embodiment 126, or salt thereof, whereinR¹ and R², together with the sulfur to which they are both attached,form a 4, 5, 6, or 7-membered heterocycloalkyl ring.

Embodiment 130: The compound of any one of Embodiments 115, 116, 117,118, 119, 126, 127, or 128, or salt thereof, wherein each R⁵ isindependently chosen from halogen, cyano, hydroxy, OR⁸, C(O)R⁸, C(O)OR⁸,and C(O)NR⁸R⁹.

Embodiment 131: The compound of Embodiment 130, or salt thereof, whereineach R⁵ is independently chosen from C(O)R⁸ and C(O)OR⁸.

Embodiment 132: The compound of either one of Embodiment 130 or 131, orsalt thereof, wherein each R⁸ is independently chosen from hydrogen,C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl, any ofwhich is optionally substituted with halo, hydroxy, and C₁₋₃alkoxy.

Embodiment 133: The compound of any one of Embodiments 1-132, or saltthereof, wherein R³ is H.

Embodiment 134: The compound of any one of Embodiments 1-132, or saltthereof, wherein R³ is chosen from C₁₋₆alkyl and C₁₋₆haloalkyl.

Embodiment 135: The compound of Embodiment 134, or salt thereof, whereinR³ is chosen from C₁₋₆alkyl and C₁₋₆fluoroalkyl.

Embodiment 136: The compound of Embodiment 135, or salt thereof, whereinR³ is chosen from methyl, fluoromethyl, difluoromethyl, andtrifluoromethyl.

Embodiment 137: The compound of Embodiment 134, or salt thereof, whereinR³ is C₁₋₆alkyl.

Embodiment 138: The compound of Embodiment 137, or salt thereof, whereinR³ is methyl.

Also provided is a pharmaceutical composition comprising a compound asdisclosed herein, or salt thereof, together with a pharmaceuticallyacceptable carrier. In certain embodiments, the compound is onedisclosed in any of the embodiments above, including in any ofEmbodiments 1-138.

In certain embodiments, the pharmaceutical composition is formulated fororal administration.

In certain embodiments, the oral pharmaceutical composition is chosenfrom a tablet and a capsule.

In certain embodiments, the pharmaceutical composition is formulated forparenteral administration.

The present disclosure also relates to a method of inhibiting at leastone ATR kinase function comprising the step of contacting ATR kinasewith a compound as described herein, or salt thereof. The cellphenotype, cell proliferation, activity of ATR kinase, change inbiochemical output produced by active ATR kinase, expression of ATRkinase, or binding of ATR kinase with a natural binding partner may bemonitored. Such methods may be modes of treatment of disease, biologicalassays, cellular assays, biochemical assays, or the like.

Also provided herein is a method of treatment of an ATR kinase-mediateddisease comprising the administration of a therapeutically effectiveamount of a compound as disclosed herein, or a salt thereof, to apatient in need thereof. In certain embodiments, the compound is onedisclosed in any of the embodiments above, including in any ofEmbodiments 1-138.

In certain embodiments, the ATR kinase-mediated disease is aproliferative disease.

In certain embodiments, the proliferative disease is amyeloproliferative disorder.

In certain embodiments, the proliferative disease is cancer.

In certain embodiments, the cancer is lymphoma.

In certain embodiments, the cancer is B cell lymphoma.

In certain embodiments, the cancer is pancreatic cancer.

Also provided herein is a compound as disclosed herein, or salt thereof,for use as a medicament.; or a pharmaceutical composition as disclosedherein for use as a medicament. In either case, in certain embodiments,the compound is one disclosed in any of the embodiments above, includingin any of Embodiments 1-138.

Also provided herein is a compound as disclosed herein, or salt thereof,for use as a medicament for the treatment of an ATR kinase-mediateddisease. In either case, in certain embodiments, the compound is onedisclosed in any of the embodiments above, including in any ofEmbodiments 1-138. In certain embodiments, the ATR kinase-mediateddisease is a proliferative disease. In certain embodiments, theproliferative disease is a myeloproliferative disorder. In certainembodiments, the proliferative disease is cancer. In certainembodiments, the cancer is lymphoma. In certain embodiments, the canceris B cell lymphoma. In certain embodiments, the cancer is pancreaticcancer.

Also provided is the use of a compound as disclosed herein, or saltthereof, as a medicament; or the use of a pharmaceutical composition asdisclosed herein as a medicament. In certain embodiments, the compoundis one disclosed in any of the embodiments above, including in any ofEmbodiments 1-138.

Also provided is the use of a compound as disclosed herein, or saltthereof, as a medicament for the treatment of an ATR kinase-mediateddisease; or the use of a pharmaceutical composition as disclosed hereinas a medicament for the treatment of an ATR kinase-mediated disease; acompound as disclosed herein, or salt thereof, for use in themanufacture of a medicament for the treatment of an ATR kinase-mediateddisease; or a pharmaceutical composition as disclosed herein for use inthe manufacture of a medicament for the treatment of an ATRkinase-mediated disease; or the use of a compound as disclosed herein,or salt thereof, for the treatment of an ATR kinase-mediated disease; orthe use of a pharmaceutical composition as disclosed herein for thetreatment of an ATR kinase-mediated disease. In certain embodiments, thecompound is one disclosed in any of the embodiments above, including inany of Embodiments 1-138. In and of these cases, in certain embodiments,the compound is one disclosed in any of the embodiments above, includingin any of Embodiments 1-138. In certain embodiments, the ATRkinase-mediated disease is a proliferative disease. In certainembodiments, the proliferative disease is a myeloproliferative disorder.In certain embodiments, the proliferative disease is cancer. In certainembodiments, the cancer is lymphoma. In certain embodiments, the canceris B cell lymphoma. In certain embodiments, the cancer is pancreaticcancer.

Also provided herein is a method of inhibition of ATR kinase comprisingcontacting ATR kinase with a compound as disclosed herein, or a saltthereof. In certain embodiments, the compound is one disclosed in any ofthe embodiments above, including in any of Embodiments 1-138.

Also provided herein is a method for achieving an effect in a patientcomprising the administration of a therapeutically effective amount of acompound as disclosed herein, or a salt thereof, to a patient, whereinthe effect is chosen from cognition enhancement. In certain embodiments,the compound is one disclosed in any of the embodiments above, includingin any of Embodiments 1-138.

Also provided is a method of modulation of an ATR kinase-mediatedfunction in a subject comprising the administration of a therapeuticallyeffective amount of a compound as disclosed herein, or salt thereof. Incertain embodiments, the compound is one disclosed in any of theembodiments above, including in any of Embodiments 1-138.

Terms

As used herein, the terms below have the meanings indicated.

When ranges of values are disclosed, and the notation “from n₁ . . . ton2” or “between n₁ . . . and n2” is used, where n₁ and n2 are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, the alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—), (—C::C—)].Examples of suitable alkenyl radicals include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, the alkyl will comprise from 1 to10 carbon atoms. In further embodiments, the alkyl will comprise from 1to 8 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, nonyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, the alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, the alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynylradicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a—C(O)N(RR′) group with R and R′ as defined herein or as defined by thespecifically enumerated “R” groups designated. The term “N-amido” asused herein, alone or in combination, refers to a RC(O)N(R′)— group,with R and R′ as defined herein or as defined by the specificallyenumerated “R” groups designated. The term “acylamino” as used herein,alone or in combination, embraces an acyl group attached to the parentmoiety through an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently chosen from hydrogen, alkyl,acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,any of which may themselves be optionally substituted. Additionally, Rand R′ may combine to form heterocycloalkyl, either of which may beoptionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C₆H4=derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group-with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” as used herein, alone or in combination, refersto a saturated or partially saturated monocyclic, bicyclic or tricyclicalkyl group wherein each cyclic moiety contains from 3 to 12 carbon atomring members and which may optionally be a benzo fused ring system whichis optionally substituted as defined herein. In certain embodiments, thecycloalkyl will comprise from 5 to 7 carbon atoms. Examples of suchcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl,2,3-dihydro-1H-indenyl, adamantyl and the like. “Bicyclic” and“tricyclic” as used herein are intended to include both fused ringsystems, such as decahydronaphthalene, octahydronaphthalene as well asthe multicyclic (multicentered) saturated or partially unsaturated type.The latter type of isomer is exemplified in general by,bicyclo[1.1.1]pentane, camphor, adamantane, and bicyclo[3.2.1]octane.“Cycloalkyl”, as used herein, alone or in combination, encompasses“bicycloalkyl”, “bridged cycloalkyl”, and “spirocycloalkyl”, as definedbelow.

The term “bicycloalkyl”, as used herein, alone or in combination, refersto a cyclic alkyl system that is characterized by the presence of twoatoms, termed “bridgehead atoms” that are connected to each other viathree bond pathways. “Bicycloalkyl” thus encompasses, by way of example,bicyclo[2.2.1]heptane, also known as norbornane, bicyclo[2.2.2]octane,bicyclo[2.2.0]hexane and bicyclo[3.3.0]octane.

The term “bridged cycloalkyl”, as used herein, alone or in combination,refers to a bicycloalkyl system in which all three of the bond pathwaysbetween bridgehead atoms contain at least one atom. “Bridged cycloalkyl”thus encompasses, by way of example, bicyclo[2.2.1]heptane, also knownas norbornane, and bicyclo[2.2.2]octane. “Bridged cycloalkyl” thus doesnot encompass bicyclo[2.2.0]hexane or bicyclo[3.3.0]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or combinations thereof, fullysaturated or containing from 1 to 3 degrees of unsaturation, consistingof the stated number of carbon atoms and from one to three heteroatomschosen from N, O, and S, and wherein the N and S atoms may optionally beoxidized and the N heteroatom may optionally be quaternized. Theheteroatom(s) may be placed at any interior position of the heteroalkylgroup. Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃.

The term “heteroaryl”, as used herein, alone or in combination, refersto a 3 to 15 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom chosenfrom N, O, and S. In certain embodiments, the heteroaryl will containfrom 1 to 4 heteroatoms as ring members. In certain embodiments, theheteroaryl will contain from 1 to 3 heteroatoms as ring members. Infurther embodiments, the heteroaryl will contain from 1 to 2 heteroatomsas ring members. In certain embodiments, the heteroaryl will containfrom 5 to 7 atoms. The term also embraces fused polycyclic groupswherein heterocyclic rings are fused with aryl rings, wherein heteroarylrings are fused with other heteroaryl rings, wherein heteroaryl ringsare fused with heterocycloalkyl rings, or wherein heteroaryl rings arefused with cycloalkyl rings. Examples of heteroaryl groups includepyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl,isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl,benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl,benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl,tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl,pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groupsinclude carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl,acridinyl, phenanthridinyl, xanthenyl and the like.

Certain heteroaryl groups are depicted below:

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated (but nonaromatic)monocyclic, bicyclic, or tricyclic heterocyclic group containing atleast one heteroatom as a ring member, wherein each the heteroatom maybe independently chosen from nitrogen, oxygen, and sulfur. In certainembodiments, the hetercycloalkyl will contain 1, 2, 3, or 4 heteroatomsas ring members. In certain embodiments, the hetercycloalkyl willcontain 1, 2, or 3 heteroatoms as ring members. In further embodiments,the hetercycloalkyl will contain 1 or 2 heteroatoms as ring members. Incertain embodiments, the hetercycloalkyl will contain from 3 to 6 ringmembers in each ring. In certain embodiments, the hetercycloalkyl willcontain from 3 to 8 ring members in each ring. In further embodiments,the hetercycloalkyl will contain from 3 to 7 ring members in each ring.In yet further embodiments, the hetercycloalkyl will contain from 5 to 6ring members in each ring. “Heterocycloalkyl” and “heterocycle” areintended to include sulfones, sulfoxides, sulfoximines, sulfimides,N-oxides of tertiary nitrogen ring members, and carbocyclic fused andbenzo fused ring systems; additionally, both terms also include systemswhere a heterocycle ring is fused to an aryl group, as defined herein,or an additional heterocycle group. Examples of heterocycle groupsinclude aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl,dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Theheterocycle groups may be optionally substituted unless specificallyprohibited. The term “heterocycloalkyl”, as used herein, alone or incombination, is understood to encompass “heterobicycloalkyl” and“bridged heterocycloalkyl”, as defined below.

The term “heterobicycloalkyl”, as used herein, alone or in combination,refers to a heterocyclic alkyl system that is characterized by thepresence of two atoms, termed “bridgehead atoms” that are connected toeach other via three bond pathways. “Bicycloalkyl” thus encompasses, byway of example, bicyclo[2.2.1]heptane, also known as norbornane,bicyclo[2.2.2]octane, bicyclo[2.2.0]hexane and bicyclo[3.3.0]octane.

The term “bridged heterocycloalkyl”, as used herein, alone or incombination, refers to a heterobicycloalkyl system in which all three ofthe bond pathways between bridgehead atoms contain at least one atom.“Bridged heterocycloalkyl” thus encompasses, by way of example,1,4-diazabicyclo[2.2.2]octane, also known as DABCO, and7-azabicyclo[2.2.1]heptane.

Bicyclic ring systems can be described using terminology that will berecognized by the person in the art. A bicyclic compound can be named asthe fusion of two ring systems. For example, “benzobenzene” isunderstood to refer to naphthalene. Unless specifically restricted, anyring fusion isomer will be embraced by this terminology. For example,“benzonaphthalene” is understood to embrace both anthracene andphenanthrene. As a further example, pyrrolopyridine is understood toembrace any compound having pyrrole fused to pyridine, and thus embraces4-azaindole, 5-azaindole, 6-azaindole, and 7-azaindole.

The term “heterobicycloalkyl”, as used herein, alone or in combination,refers to a saturated, partially unsaturated, or fully unsaturated (butnonaromatic) cyclic alkyl system, containing at least one heteroatom asa ring member, that is characterized by the presence of two atoms,termed “bridgehead atoms” that are connected to each other via threebond pathways. “Heterobicycloalkyl” thus encompasses, by way of example,7-azabicyclo[2.2.1]heptane, 1,4-diazabicyclo[2.2.2]octane, also referredto as “DABCO”, 1-azabicyclo[2.2.0]hexane, and 3-azabicyclo[3.3.0]octane.

The term “bridged heterocycloalkyl”, as used herein, alone or incombination, refers to a heterobicycloalkyl system in which all three ofthe bond pathways between bridgehead atoms contain at least one atom.“Bridged heterocycloalkyl” thus encompasses, by way of example,7-azabicyclo[2.2.1]heptane, 1,4-diazabicyclo[2.2.2]octane, also referredto as “DABCO”, but not 1-azabicyclo[2.2.0]hexane, or3-azabicyclo[3.3.0]octane.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group. Examples of hydroxyalkyl groups include hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, and 2-hydroxy-2-propyl.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently chosen from carbon, nitrogen, oxygen and sulfur.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms (i.e., C₁-C₆ alkyl).

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, either of which may be optionally substituted asprovided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four the members may be heteroatomschosen from N, O, and S, or 2) bicyclic heteroaryl, wherein each of thefused rings comprises five or six ring members, comprising between themone to four heteroatoms chosen from N, O, and S.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members(i.e., C₃-C₆ cycloalkyl). Lower cycloalkyls may be unsaturated. Examplesof lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomschosen from N, O, and S (i.e., C₃-C₆ heterocycloalkyl). Examples oflower heterocycloalkyls include pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lowerheterocycloalkyls may be unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently chosen from hydrogen andlower alkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The term “spirocycloalkyl”, as used herein, alone or in combination,refers to an alkyl group having two rings that has a single atom commonto both rings. Examples of spirocycloalkyl systems includespiro[3.3]heptane and spiro[4.4]nonane.

The term “spiroheterocycloalkyl”, as used herein, alone or incombination, refers to a heteroalkyl group having two rings that has asingle atom common to both rings. Examples of spirocycloalkyl systemsinclude 2-azaspiro[3.3]heptane and 3-azaspiro[4.4]nonane.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(═O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(═O)₂NRR′, group, with R and R′as defined herein.

The term “sulfimide” refers to a RS(═NR′)R″ group with R, R′, and R″ asdefined herein.

The term “sulfoximine” refers to a RS(═O)(═NR′)R″ group with R, R′, andR″ as defined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X isa halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethysilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that the group isabsent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently chosen from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Wherestructurally feasible, two substituents may be joined together to form afused five-, six-, or seven-membered carbocyclic or heterocyclic ringconsisting of zero to three heteroatoms, for example formingmethylenedioxy or ethylenedioxy. An optionally substituted group may beunsubstituted (e.g., —CH₂CH₃), fully substituted (e.g., —CF₂CF₃),monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywherein-between fully substituted and monosubstituted (e.g., —CH₂CF₃). Wheresubstituents are recited without qualification as to substitution, bothsubstituted and unsubstituted forms are encompassed. Where a substituentis qualified as “substituted,” the substituted form is specificallyintended. Additionally, different sets of optional substituents to aparticular moiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, or the term R″, appearing by itself andwithout a number designation, unless otherwise defined, refers to amoiety chosen from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl,heteroaryl and heterocycloalkyl, any of which may be optionallysubstituted. Such R, R′ and R″ groups should be understood to beoptionally substituted as defined herein. Whether an R group has anumber designation or not, every R group, including R, R′ and R″ wheren=(1, 2, 3, . . . n), every substituent, and every term should beunderstood to be independent of every other in terms of selection from agroup. Should any variable, substituent, or term (e.g. aryl,heterocycle, R, etc.) occur more than one time in a formula or genericstructure, its definition at each occurrence is independent of thedefinition at every other occurrence. Those of skill in the art willfurther recognize that certain groups may be attached to a parentmolecule or may occupy a position in a chain of elements from either endas written. For example, an unsymmetrical group such as —C(O)N(R)— maybe attached to the parent moiety at either the carbon or the nitrogen.

The term “enantiomer”, as used herein, alone or in combination, refersto one of a pair of compounds that differ in absolute stereochemistry atevery stereocenter. Each enantiomer in a pair of compounds is thus themirror image of the other enantiomer.

The term “epimer”, as used herein, alone or in combination, refers toone of a pair of compounds that differ in absolute stereochemistry at asingle stereocenter.

The term “diastereomer”, as used herein, alone or in combination, refersto one of a pair of compounds that neither have identicalstereochemistry nor are enantiomers of each other.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the disclosure encompasses all stereochemicalisomeric forms, including diastereomeric, enantiomeric, and epimericforms, as well as D-isomers and L-isomers, and mixtures thereof.Individual stereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentdisclosure includes all cis, trans, syn, anti, entgegen (E), andzusammen (Z) isomers as well as the appropriate mixtures thereof.Additionally, compounds may exist as tautomers; all tautomeric isomersare provided by this disclosure. Additionally, the compounds disclosedherein can exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. In general, the solvated forms are considered equivalent to theunsolvated forms.

Certain of the compounds disclosed herein can exist as a mixture of twodiastereomers. In some embodiments, the two diastereomers are present inequal amounts. In some embodiments, the compound contains 60% or more ofthe major diastereomer. In some embodiments, the compound contains 70%or more of the major diastereomer. In some embodiments, the compoundcontains 80% or more of the major diastereomer. In some embodiments, thecompound contains 90% or more of the major diastereomer. In someembodiments, the compound contains 95% or more of the majordiastereomer. In some embodiments, the compound contains 98% or more ofthe major diastereomer.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms, and causes the human or animal tohave a reduced duration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

“ATR inhibitor” is used herein to refer to a compound that exhibits anIC₅₀ with respect to ATR kinase activity of no more than about 10 μM andmore typically not more than about 5 μM, as measured in the ATR/ATRIPbiochemical assay or in the ATR kinase pCHK1 cellular assay describedgenerally herein. “IC₅₀” is that concentration of inhibitor whichreduces to half-maximal level the activity of an enzyme (e.g., ATRkinase), or the ATR-induced phosphorylation of CHK1 at Serine 345 incells. Certain compounds disclosed herein have been discovered toexhibit inhibition against ATR kinase. In certain embodiments, compoundswill exhibit an IC₅₀ with respect to ATR kinase of no more than about 1μM; in further embodiments, compounds will exhibit an IC₅₀ with respectto ATR kinase of no more than about 2 μM; in yet further embodiments,compounds will exhibit an IC50 with respect to ATR kinase of not morethan about 1 μM; in yet further embodiments, compounds will exhibit anIC₅₀ with respect to ATR kinase of not more than about 500 nM; in yetfurther embodiments, compounds will exhibit an IC₅₀ with respect to ATRkinase of not more than about 200 nM; in yet further embodiments,compounds will exhibit an IC₅₀ with respect to ATR kinase of not morethan about 100 nM, as measured in the ATR kinase assay described herein.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder oron the effecting of a clinical endpoint.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without undue toxicity,irritation, and allergic response, are commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. Treatment may also be preemptive in nature, i.e.,it may include prevention of disease. Prevention of a disease mayinvolve complete protection from disease, for example as in the case ofprevention of infection with a pathogen, or may involve prevention ofdisease progression. For example, prevention of a disease may not meancomplete foreclosure of any effect related to the diseases at any level,but instead may mean prevention of the symptoms of a disease to aclinically significant or detectable level. Prevention of diseases mayalso mean prevention of progression of a disease to a later stage of thedisease. In certain embodiments, the treatment is not prophylactic. Forexample, treatment is undertake after a diagnosis of disease or theappearance of symptoms of the disease.

The term “patient” is generally synonymous with the term “subject” andincludes all mammals including humans. Examples of patients includehumans, livestock such as cows, goats, sheep, pigs, and rabbits, andcompanion animals such as dogs, cats, rabbits, and horses. Preferably,the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in i Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound.

Salts

The compounds disclosed herein can exist as salts, includingpharmaceutically acceptable salts. The present disclosure includescompounds listed above in the form of salts, including acid additionsalts. Suitable salts include those formed with both organic andinorganic acids. Such acid addition salts will normally bepharmaceutically acceptable. However, salts of non-pharmaceuticallyacceptable salts may be of utility in the preparation and purificationof the compound in question. Basic addition salts may also be formed andbe pharmaceutically acceptable.

The term “pharmaceutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent disclosure contemplates sodium, potassium, magnesium, andcalcium salts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of pharmaceutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

Formulations

While it may be possible for the compounds of the subject disclosure, orsalts thereof, to be administered as the raw chemical, it is alsopossible to present them as a pharmaceutical formulation. Accordingly,provided herein are pharmaceutical formulations which comprise one ormore of certain compounds disclosed herein, or one or morepharmaceutically acceptable salts, esters, prodrugs, amides, or solvatesthereof, together with one or more pharmaceutically acceptable carriersthereof and optionally one or more other therapeutic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof. Proper formulation is dependent upon the route ofadministration chosen. Any of the well-known techniques, carriers, andexcipients may be used as suitable and as understood in the art. Thepharmaceutical compositions disclosed herein may be manufactured in anymanner known in the art, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or compression processes.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject disclosure or a pharmaceutically acceptable salt, ester, amide,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds (including in the form of compositions describedherein) disclosed herein may be administered topically, that is bynon-systemic administration. This includes the application of a compounddisclosed herein externally to the epidermis or the buccal cavity andthe instillation of such a compound into the ear, eye and nose, suchthat the compound does not significantly enter the blood stream. Incontrast, systemic administration refers to oral, intravenous,intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

For administration by inhalation, compounds (including in the form ofcompositions described herein) may be conveniently delivered from aninsufflator, nebulizer pressurized packs or other convenient means ofdelivering an aerosol spray. Pressurized packs may comprise a suitablepropellant such as dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, the compounds according tothe disclosure may take the form of a dry powder composition, forexample a powder mix of the compound and a suitable powder base such aslactose or starch. The powder composition may be presented in unitdosage form, in for example, capsules, cartridges, gelatin or blisterpacks from which the powder may be administered with the aid of aninhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds (including in the form of compositions described herein) maybe administered orally or via injection at a dose of from 0.1 to 500mg/kg per day. The dose range for adult humans is generally from 5 mg to2 g/day. Tablets or other forms of presentation provided in discreteunits may conveniently contain an amount of one or more compounds whichis effective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds (including in the form of compositions described herein)can be administered in various modes, e.g. orally, topically, or byinjection. The precise amount of compound administered to a patient willbe the responsibility of the attendant physician. The specific doselevel for any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diets, time of administration, route ofadministration, rate of excretion, drug combination, the precisedisorder being treated, and the severity of the indication or conditionbeing treated. Also, the route of administration may vary depending onthe condition and its severity.

Combinations and Combination Therapies

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, or prodrug thereof or composition thereof) in combinationwith another therapeutic agent. By way of example only, if one of theside effects experienced by a patient upon receiving one of thecompounds herein is hypertension, then it may be appropriate toadminister an anti-hypertensive agent in combination with the initialtherapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may onlyhave minimal therapeutic benefit, but in combination with anothertherapeutic agent, the overall therapeutic benefit to the patient isenhanced). Or, by way of example only, the benefit of experienced by apatient may be increased by administering one of the compounds describedherein with another therapeutic agent (which also includes a therapeuticregimen) that also has therapeutic benefit. By way of example only, in atreatment for diabetes involving administration of one of the compoundsdescribed herein, increased therapeutic benefit may result by alsoproviding the patient with another therapeutic agent for diabetes. Inany case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may simply beadditive of the two therapeutic agents or the patient may experience asynergistic benefit.

The compounds of the present disclosure can be used, alone or incombination with other pharmaceutically active compounds, to treatconditions such as those previously described hereinabove. Thecompound(s) of the present disclosure and other pharmaceutically activecompound(s) can be administered simultaneously (either in the samedosage form or in separate dosage forms) or sequentially. Accordingly,in one embodiment, the present disclosure comprises methods for treatinga condition by administering to the subject a therapeutically-effectiveamount of one or more compounds of the present disclosure and one ormore additional pharmaceutically active compounds.

In another embodiment, there is provided a pharmaceutical compositioncomprising one or more compounds of the present disclosure, one or moreadditional pharmaceutically active compounds, and a pharmaceuticallyacceptable carrier.

In another embodiment, the one or more additional pharmaceuticallyactive compounds is chosen from anti-cancer drugs, anti-proliferativedrugs, and anti-inflammatory drugs.

ATR inhibitor compositions described herein are also optionally used incombination with other therapeutic reagents that are chosen for theirtherapeutic value for the condition to be treated. In general, thecompounds described herein and, in embodiments where combination therapyis employed, other agents do not have to be administered in the samepharmaceutical composition and, because of different physical andchemical characteristics, are optionally administered by differentroutes. The initial administration is generally made according toestablished protocols and then, based upon the observed effects, thedosage, modes of administration and times of administration subsequentlymodified. In certain instances, it is appropriate to administer an ATRinhibitor compound, as described herein, in combination with anothertherapeutic agent. By way of example only, the therapeutic effectivenessof an ATR inhibitor is enhanced by administration of another therapeuticagent (which also includes a therapeutic regimen) that also hastherapeutic benefit. Regardless of the disease, disorder or conditionbeing treated, the overall benefit experienced by the patient is eithersimply additive of the two therapeutic agents or the patient experiencesan enhanced (i.e., synergistic) benefit. Alternatively, if a compounddisclosed herein has a side effect, it may be appropriate to administeran agent to reduce the side effect; or the therapeutic effectiveness ofa compound described herein may be enhanced by administration of anadjuvant.

Therapeutically effective dosages vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically effective dosages of drugs and other agents for use incombination treatment regimens are documented methodologies. Combinationtreatment further includes periodic treatments that start and stop atvarious times to assist with the clinical management of the patient. Inany case, the multiple therapeutic agents (one of which is an ATRinhibitor as described herein) may be administered in any order, orsimultaneously. If simultaneously, the multiple therapeutic agents areoptionally provided in a single, unified form, or in multiple forms (byway of example only, either as a single pill or as two separate pills).

In another embodiment, an ATR inhibitor is optionally used incombination with procedures that provide additional benefit to thepatient. An ATR inhibitor and any additional therapies are optionallyadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing anATR inhibitor varies in some embodiments. Thus, for example, an ATRinhibitor is used as a prophylactic and is administered continuously tosubjects with a propensity to develop conditions or diseases in order toprevent the occurrence of the disease or condition. An ATR inhibitor andcompositions are optionally administered to a subject during or as soonas possible after the onset of the symptoms. While embodiments of thepresent disclosure have been shown and described herein, it will beobvious to those skilled in the art that such embodiments are providedby way of example only. Numerous variations, changes, and substitutionswill now occur to those skilled in the art without departing from thedisclosure. It should be understood that in some embodiments of thedisclosure various alternatives to the embodiments described herein areemployed in practicing the disclosure.

An ATR inhibitor can be used in combination with anti-cancer drugs,including but not limited to the following classes: alkylating agsents,anti-metabolites, plant alkaloids and terpenoids, topoisomeraseinhibitors, cytotoxic antibiotics, angiogenesis inhibitors and tyrosinekinase inhibitors.

For use in cancer and neoplastic diseases an ATR inhibitor may beoptimally used together with one or more of the following non-limitingexamples of anti-cancer agents:

-   -   1) inhibitors or modulators of a protein involved in one or more        of the DNA damage repair (DDR) pathways such as:        -   a. PARP1/2, including, but not limited to: olaparib,            niraparib, rucaparib;        -   b. checkpoint kinase 1 (CHK1), including, but not limited            to: UCN-01, AZD7762, PF477736, SCH900776, MK-8776,            LY2603618, V158411, and EXEL-9844;        -   c. checkpoint kinase 2 (CHK2), including, but not limited            to: PV1019, NSC 109555, and VRX0466617;        -   d. dual CHK1/CHK2, including, but not limited to: XL-844,            AZD7762, and PF-473336;        -   e. WEE1, including, but not limited to: MK-1775 and            PD0166285;        -   f. ATM, including, but not limited to KU-55933,        -   g. DNA-dependent protein kinase, including, but not limited            to NU7441 and M3814; and        -   h. Additional proteins involved in DDR;    -   2) Inhibitors or modulators of one or more immune checkpoints,        including, but not limited to:        -   a. PD-1 inhibitors such as nivolumab (OPDIVO), pembrolizumab            (KEYTRUDA), pidilizumab (CT-011), and AMP-224 (AMPLIMMUNE);        -   b. PD-L1 inhibitors such as Atezolizumab (TECENTRIQ),            Avelumab (Bavencio), Durvalumab (Imfinzi), MPDL3280A            (Tecentriq), BMS-936559, and MEDI4736;        -   c. anti-CTLA-4 antibodies such as ipilimumab (YERVOY) and            CP-675,206 (TREMELIMUMAB);        -   d. inhibitors of T-cell immunoglobulin and mucin domain 3            (Tim-3);        -   e. inhibitors of V-domain Ig suppressor of T cell activation            (Vista);        -   f. inhibitors of band T lymphocyte attenuator (BTLA);        -   g. inhibitors of lymphocyte activation gene 3 (LAG3); and        -   h. inhibitors of T cell immunoglobulin and immunoreceptor            tyrosine-based inhibitory motif domain (TIGIT);    -   3) telomerase inhibitors or telomeric DNA binding compounds;    -   4) alkylating agents, including, but not limited to:        chlorambucil (LEUKERAN), oxaliplatin (ELOXATIN), streptozocin        (ZANOSAR), dacarbazine, ifosfamide, lomustine (CCNU),        procarbazine (MATULAN), temozolomide (TEMODAR), and thiotepa;    -   5) DNA crosslinking agents, including, but not limited to:        carmustine, chlorambucil (LEUKERAN), carboplatin (PARAPLATIN),        cisplatin (PLATIN), busulfan (MYLERAN), melphalan (ALKERAN),        mitomycin (MITOSOL), and cyclophosphamide (ENDOXAN);    -   6) anti-metabolites, including, but not limited to: cladribine        (LEUSTATIN), cytarbine, (ARA-C), mercaptopurine (PURINETHOL),        thioguanine, pentostatin (NIPENT), cytosine arabinoside        (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU,        CARAC), capecitabine (XELODA), leucovorin (FUSILEV),        methotrexate (RHEUMATREX), and raltitrexed;    -   7) antimitotics, which are often plant alkaloids and terpenoids,        or derivateves thereof including but limited to: taxanes such as        docetaxel (TAXITERE), paclitaxel (ABRAXANE, TAXOL), vinca        alkaloids such as vincristine (ONCOVIN), vinblastine, vindesine,        and vinorelbine (NAVELBINE);    -   8) topoisomerase inhibitors, including, but not limited to:        amsacrine, camptothecin (CTP), genisten, irinotecan (CAMPTOSAR),        topotecan (HYCAMTIN), doxorubicin (ADRIAMYCIN), daunorubicin        (CERUBIDINE), epirubicin (ELLENCE), ICRF-193, teniposide        (VUMON), mitoxantrone (NOVANTRONE), and etoposide (EPOSIN);    -   9) DNA replication inhibitors, including, but not limited to:        fludarabine (FLUDARA), aphidicolin, ganciclovir, and cidofovir;    -   10) ribonucleoside diphosphate reductase inhibitors, including,        but not limited to: hydroxyurea;    -   11) transcription inhibitors, including, but not limited to:        actinomycin D (dactinomycin, COSMEGEN) and plicamycin        (mithramycin);    -   12) DNA cleaving agents, including, but not limited to:        bleomycin (BLENOXANE), idarubicin,    -   13) cytotoxic antibiotics, including, but not limited to:        actinomycin D (dactinomycin, COSMEGEN),    -   14) aromatase inhibitors, including, but not limited to:        aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA),        vorozole (RIVIZOR), and exemestane (AROMASIN);    -   15) angiogenesis inhibitors, including, but not limited to:        genistein, sunitinib (SUTENT), and bevacizumab (AVASTIN);    -   16) anti-steroids and anti-androgens, including, but not limited        to: aminoglutethimide (CYTADREN), bicalutamide (CASODEX),        cyproterone, flutamide (EULEXIN), nilutamide (NILANDRON);    -   17) tyrosine kinase inhibitors, including, but not limited to:        imatinib (GLEEVEC), erlotinib (TARCEVA), lapatininb (TYKERB),        sorafenib (NEXAVAR), and axitinib (INLYTA);    -   18) mTOR inhibitors, including, but not limited to: everolimus,        temsirolimus (TORISEL), and sirolimus;    -   19) monoclonal antibodies, including, but not limited to:        trastuzumab (HERCEPTIN) and rituximab (RITUXAN);    -   20) apoptosis inducers such as cordycepin;    -   21) protein synthesis inhibitors, including, but not limited to:        clindamycin, chloramphenicol, streptomycin, anisomycin, and        cycloheximide;    -   22) antidiabetics, including, but not limited to: metformin and        phenformin;    -   23) antibiotics, including, but not limited to:        -   a. tetracyclines, including, but not limited to:            doxycycline;        -   b. erythromycins, including, but not limited to:            azithromycin;        -   c. glycylglycines, including, but not limited to:            tigecyline;        -   d. antiparasitics, including, but not limited to: pyrvinium            pamoate;        -   e. beta-lactams, including, but not limited to the            penicillins and cephalosporins;        -   f. anthracycline antibiotics, including, but not limited to:            daunorubicin and doxorubicin;        -   g. other antibiotics, including, but not limited to:            chloramphenicol, mitomycin C, and actinomycin;    -   24) antibody therapeutical agents, including, but not limited        to: muromonab-CD3, infliximab (REMICADE), adalimumab (HUMIRA),        omalizumab (XOLAIR), daclizumab (ZENAPAX), rituximab (RITUXAN),        ibritumomab (ZEVALIN), tositumomab (BEXXAR), cetuximab        (ERBITUX), trastuzumab (HERCEPTIN), ADCETRIS, alemtuzumab        (CAMPATH-1H), Lym-1 (ONCOLYM), ipilimumab (YERVOY), vitaxin,        bevacizumab (AVASTIN), and abciximab (REOPRO); and    -   25) other agents, such as Bacillus Calmette-Gudrin (B-C-G)        vaccine; buserelin (ETILAMIDE); chloroquine (ARALEN);        clodronate, pamidronate, and other bisphosphonates; colchicine;        demethoxyviridin; dichloroacetate; estramustine; filgrastim        (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX);        interferon; leucovorin; leuprolide (LUPRON); levamisole;        lonidamine; mesna; metformin; mitotane (o,p′-DDD, LYSODREN);        nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer        (particularly in combination with photo- and radiotherapy);        suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic        steroids such as fluoxymesterone (HALOTESTIN); estrogens such as        estradiol, diethylstilbestrol (DES), and dienestrol; progestins        such as medroxyprogesterone acetate (MPA) and megestrol; and        testosterone.

In any case, the multiple therapeutic agents (at least one of which is acompound disclosed herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

Thus, in another aspect, certain embodiments provide methods fortreating ATR kinase-mediated disorders in a human or animal subject inneed of such treatment comprising administering to the subject an amountof a compound disclosed herein, or a salt thereof effective to reduce orprevent the disorder in the subject, in combination with at least oneadditional agent for the treatment of the disorder that is known in theart. In a related aspect, certain embodiments provide therapeuticcompositions comprising at least one compound disclosed herein incombination with one or more additional agents for the treatment of ATRkinase-mediated disorders.

Specific diseases to be treated by the compounds, compositions, andmethods disclosed herein include proliferative and hyperproliferativediseases, including cancer.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

Provided below are exemplary embodiments of the disclosure.

Embodiment I-1: A compound of structural Formula (I):

or a salt thereof, wherein:

-   -   R¹ and R² are independently selected from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, aryl, and        heteroaryl, each of which is optionally substituted with one or        more RS groups, or R¹ and R², together with the sulfur to which        they are both attached, form a heterocycloalkyl ring which is        optionally substituted with one or more R⁵ groups;    -   R³ is selected from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   R⁴ is selected from C₅₋₁₀aryl and C₅₋₁₀heteroaryl, each of which        is optionally substituted with one or more R⁶ groups;    -   each R⁵ is independently selected from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl,        hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸, NR⁷C(O)NR⁸R⁹, C(O)R⁸,        C(O)OR⁸, and C(O)NR⁸R⁹;    -   each R⁶ is independently selected from NR¹¹R¹², halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently selected from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and heterocycloalkyl and is        optionally substituted with halo, hydroxy, C₁₋₃alkyl, C₁₋₃        haloalkyl, and C₁₋₃alkoxy; or any two of R⁷, R⁸ and R⁹, together        with the atom to which they are both attached can form a 3-7        membered cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently selected from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl, and heterocycloalkyl and is        optionally substituted with one or more groups selected from        halo, hydroxy and alkoxy; or any two of R¹⁰, R¹¹ and R¹²,        together with the atom to which they are both attached, can form        a 3-7 membered cycloalkyl or heterocycloalkyl ring.

Embodiment I-2: The compound as recited in Embodiment I-1, wherein R³ isC₁₋₆alkyl.

Embodiment I-3: The compound as recited in Embodiment I-2, wherein R³ ismethyl.

Embodiment II-4: A compound of structural Formula (II):

or a salt thereof, wherein:

-   -   R¹ and R² are independently selected from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, aryl, and        heteroaryl, each of which is optionally substituted with one or        more RS groups, or R¹ and R², together with the sulfur to which        they are both attached, form a heterocycloalkyl ring which is        optionally substituted with one or more R⁵ groups;    -   R³ is selected from hydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;    -   R⁴ is selected from C₅₋₁₀aryl or C₅₋₁₀ heteroaryl and is        optionally substituted with one or more R⁶ groups;    -   each R⁵ is independently selected from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl,        hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸, NR⁷C(O)NR⁸R⁹, C(O)R⁸,        C(O)OR⁸, and C(O)NR⁸R⁹;    -   each R⁶ is independently selected from NR¹¹R¹², halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl,        hydroxyalkyl, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹²,        C(O)R¹¹, C(O)OR¹¹, and C(O)NR¹¹R¹²;    -   each R⁷, R⁸ and R⁹ is independently selected from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl and heterocycloalkyl and is optionally        substituted with halo, hydroxy, C₁₋₃alkyl, C₁₋₃ haloalkyl and        C₁₋₃alkoxy; or any two of R⁷, R⁸ and R⁹, together with the atom        to which they are both attached can form a 3-7 membered        cycloalkyl or heterocycloalkyl ring; and    -   each R¹⁰, R¹¹ and R¹² is independently selected from hydrogen,        C₁₋₄alkyl, C₃₋₆cycloalkyl and heterocycloalkyl and is optionally        substituted with one or more groups selected from halo, hydroxy        and alkoxy; or any two of R¹⁰, R¹¹ and R¹², together with the        atom to which they are both attached, can form a 3-7 membered        cycloalkyl or heterocycloalkyl ring.

Embodiment II-5: The compound as recited in Embodiment II-4, wherein R³is C₁₋₆alkyl.

Embodiment II-6: The compound as recited in Embodiment II-5, wherein R³is methyl.

Embodiment II-7: The compound as recited in Embodiment II-6, wherein R⁴is C₅₋₁₀heteroaryl and is optionally substituted with one or more R⁶groups.

Embodiment II-8: The compound as recited in Embodiment II-7, wherein R⁴is selected from indole, pyrrolopyridine, pyrazolopyridine,imidazolopyridine, pyrrolopyrazine, pyrazolopyrazine, pyrrolopyrimidine,pyrazolopyrimidine, imidazolopyrimidine, pyrrolopyridazine,pyrazolopyridazine, and imidazolopyridazine, and is optionallysubstituted with one or more R⁶ groups.

Embodiment II-9: The compound as recited in Embodiment II-8, wherein R⁴is selected from 1H-pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-c]pyridazine,7H-pyrrolo[2,3-d]pyrimidine, and 5H-pyrrolo[2,3-b]pyrazine and isoptionally substituted with one, two, or three R⁶ groups.

Embodiment II-10: The compound as recited in Embodiment II-9, wherein R⁴is 1H-pyrrolo[2,3-b]pyridine and is optionally substituted with one ortwo R⁶ groups.

Embodiment II-11: The compound as recited in Embodiment II-10, whereineach R⁶ is independently selected from NR¹¹R¹², halogen, cyano, hydroxy,oxo, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹,C(O)OR¹¹, and C(O)NR¹¹R¹².

Embodiment II-12: The compound as recited in Embodiment II-11, whereineach R⁶ is independently selected from NR¹¹R¹², halogen, cyano, hydroxy,and oxo.

Embodiment II-13: The compound as recited in Embodiment II-12, whereinR⁴ is selected from

Embodiment II-14: The compound as recited in Embodiment II-13, wherein

-   -   R¹ and R² are independently selected from C₁₋₄alkyl,        C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆ heterocycloalkyl, aryl, and        heteroaryl and are optionally substituted with one or two R⁵        groups, or R¹ and R², together with the sulfur to which they are        both attached, form a heterocycloalkyl ring which is optionally        substituted with one or two R⁵ groups;    -   each R⁵ is independently selected from NR⁸R⁹, halogen, cyano,        hydroxy, oxo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl,        hydroxyalkyl, OR⁸, NRC(O)R⁸, NR⁷C(O)OR⁸, NR⁷C(O)NR⁸R⁹, C(O)R⁸,        C(O)OR⁸, and C(O)NR⁸R⁹.

Embodiment II-15: The compound as recited in Embodiment II-14, whereineach R⁵ is independently selected from alkyl, haloalkyl, cycloalkyl,heterocycloalkyl, hydroxyalkyl, OR⁸, NR⁷C(O)R⁸, NR⁷C(O)OR⁸,NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹.

Embodiment II-16: The compound as recited in Embodiment II-15, whereineach R⁵ is independently selected from C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹.

Embodiment II-17: The compound as recited in Embodiment II-16, whereinR¹ and R² are independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, C₃₋₆heterocycloalkyl, aryl, and heteroaryl and areoptionally substituted with one or two R⁵ groups.

Embodiment II-18: The compound as recited in Embodiment II-17, whereinR¹ and R² are independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl,C₃₋₆cycloalkyl, and C₃₋₆heterocycloalkyl and are optionally substitutedwith one or two R⁵ groups.

Embodiment II-19: The compound as recited in Embodiment II-17, whereinR¹ and R² are independently selected from C₁₋₄alkyl and C₃₋₆cycloalkyl.

Embodiment II-20: The compound as recited in Embodiment II-17, whereinR¹ and R², together with the sulfur to which they are both attached,forms a heterocycloalkyl ring and is optionally substituted with one ortwo R⁵ groups.

Embodiment C-21: The compound as recited in Embodiment I-1, wherein thestructure is selected from

Embodiment C-22: The compound as recited in Embodiment I-1 for use as amedicament.

Embodiment C-23: The compound as recited in Embodiment I-1 for use inthe manufacture of a medicament for the prevention or treatment of adisease or condition ameliorated by the inhibition of ATR kinase.

Embodiment C-24: The compound as recited in Embodiment C-23, wherein thedisease is cancer.

Embodiment C-25: The compound as recited in Embodiment C-24, wherein thecancer is a chemotherapy-resistant cancer.

Embodiment C-26: The compound as recited in Embodiment C-24, wherein thecancer is a radiotherapy-resistant cancer.

Embodiment C-27: The compound as recited in Embodiment C-24, wherein thecancer is an ALT-positive cancer.

Embodiment C-28: The compound as recited in Embodiment C-24, wherein thecancer is a sarcoma.

Embodiment C-29: The compound as recited in Embodiment C-24, wherein thecancer is selected from osteosarcoma and glioblastoma.

Embodiment C-30: The compound as recited in Embodiment C-24, wherein thecancer is selected from lung cancer, head and neck cancer, pancreaticcancer, gastric cancer, and brain cancer.

Embodiment C-31: The compound as recited in Embodiment C-24, wherein thecancer is selected from non-small cell lung cancer, small cell lungcancer, pancreatic cancer, biliary tract cancer, head and neck cancer,bladder cancer, colorectal cancer, glioblastoma, esophageal cancer,breast cancer, hepatocellular carcinoma, and ovarian cancer.

Embodiment C-32: The compound as recited in Embodiment C-24, wherein thecancer has a defect in a base excision repair protein.

Embodiment C-33: A pharmaceutical composition comprising a compound asrecited in Embodiment I-1 together with a pharmaceutically acceptablecarrier.

Embodiment M-34: A method of sensitizing cells to DNA-damaging agentscomprising administering to a patient a compound as recited inEmbodiment I-1.

Embodiment M-35: A method of preventing cell repair from DNA damagecomprising administering to a patient a compound as recited inEmbodiment I-1.

Embodiment M-36: A method of inhibition of ATR kinase comprisingcontacting ATR kinase with a compound as recited in Embodiment I-1.

Embodiment M-37: A method of treatment of an ATR kinase-mediated diseasecomprising the administration of a therapeutically effective amount of acompound as recited in Embodiment I-1 to a patient in need thereof.

Embodiment M-38: The method as recited in Embodiment M-37, wherein thedisease is cancer.

Embodiment M-39: The method as recited in Embodiment M-38, wherein thecancer is a chemotherapy-resistant cancer.

Embodiment M-40: The method as recited in Embodiment M-38, wherein thecancer is a radiotherapy-resistant cancer.

Embodiment M-41: The method as recited in Embodiment M-38, wherein thecancer is an ALT-positive cancer.

Embodiment M-42: The method as recited in Embodiment M-38, wherein thecancer is a sarcoma.

Embodiment M-43: The method as recited in Embodiment M-38, wherein thecancer is selected from osteosarcoma and glioblastoma.

Embodiment M-44: The method as recited in Embodiment M-38, wherein thecancer is selected from lung cancer, head and neck cancer, pancreaticcancer, gastric cancer, and brain cancer.

Embodiment M-45: The method as recited in Embodiment M-38, wherein thecancer is selected from non-small cell lung cancer, small cell lungcancer, pancreatic cancer, biliary tract cancer, head and neck cancer,bladder cancer, colorectal cancer, glioblastoma, esophageal cancer,breast cancer, hepatocellular carcinoma, and ovarian cancer.

Embodiment M-46: The method as recited in Embodiment M-38, wherein thecancer has a defect in a base excision repair protein.

Embodiment M-47: The method as recited in Embodiment M-38, wherein thecancer has defects in the ATM signaling cascade.

Embodiment M-48: The method as recited in Embodiment M-47, wherein thedefect is altered expression or activity of one or more of thefollowing: TM, p53, CHK2, MRE11, RAD50, NBS 1, 53BP1, MDC1, H2AX,MCPH1/BRIT1, CTIP, or SMC1.

Embodiment M-49: The method as recited in Embodiment M-38, furthercomprising administering to the patient another therapeutic agent,wherein the other therapeutic agent inhibits or modulates a baseexcision repair protein.

Embodiment M-50: A method of treatment of an ATR kinase-mediated diseasecomprising the administration of:

-   -   a. a therapeutically effective amount of a compound as recited        in Embodiment I-1; and    -   b. another therapeutic agent.

Embodiment M-51: The method as recited in Embodiment M-50, wherein theother therapeutic agent is a CHK1 inhibitor.

Embodiment M-52: The method as recited in Embodiment M-50, wherein theCHK1 inhibitor is selected from MK-8776, LY2603618, V158411, PF-477736,UCN-01, and AZD7762.

Embodiment M-53: The method as recited in Embodiment M-50, wherein theother therapeutic agent is a DNA-damaging agent.

Embodiment M-54: The method as recited in Embodiment M-53, wherein theDNA-damaging agent is selected from ionizing radiation, radiomimeticneocarzinostatin, a platinating agent, a Topo I inhibitor, a Topo IIinhibitor, an antimetabolite, an alkylating agent, an alkyl sulphonate,and an antibiotic.

Embodiment M-55: The method as recited in Embodiment M-54, wherein theplatinating agent is selected from cisplatin, oxaliplatin, carboplatin,nedaplatin, lobaplatin, triplatin tetranitrate, picoplatin, satraplatin,ProLindac, and aroplatin.

Embodiment M-56: The method as recited in Embodiment M-54, wherein theTopo I inhibitor is selected from camptothecin, topotecan,irinotecan/SN38, rubitecan and belotecan.

Embodiment M-57: The method as recited in Embodiment M-54, wherein theTopo II inhibitor is selected from etoposide, daunorubicin, doxorubicin,clarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin,zorubicin and teniposide.

Embodiment M-58: The method as recited in Embodiment M-54, wherein theantimetabolite is selected from aminopterin, methotrexate, pemetrexed,raltitrexed, pentostatin, cladribine, clofarabine, fludarabine,thioguanine, mercaptopurine, fluorouracil, capecitabine, tegafur,carmofur, floxuridine, cytarabine, gemcitabine, azacitidine, andhydroxyurea.

Embodiment M-59: The method as recited in Embodiment M-54, wherein thealkylating agent is selected from mechlorethamine, cyclophosphamide,ifosfamide, trofosfamide, chlorambucil, melphalan, prednimustine,bendamustine, uramustine, estramustine, carmustine, lomustine,semustine, fotemustine, nimustine, ranimustine, streptozocin, busulfan,mannosulfan, treosulfan, carboquone, thioTEPA, triaziquone,triethylenemelamine, procarbazine, dacarbazine, temozolomide,altretamine, mitobronitol, actinomycin, bleomycin, mitomycin, andplicamycin.

Embodiment M-60: The method as recited in Embodiment M-38, wherein themethod further comprises administering non-chemical methods of cancertreatment.

Embodiment M-61: The method as recited in Embodiment M-60, wherein themethod further comprises administering radiation therapy.

Embodiment M-62: The method as recited in Embodiment M-60, wherein themethod further comprises administering surgery, thermoablation, focusedultrasound therapy, cryotherapy, or any combination thereof.

Embodiment M-63: A method of increasing the sensitivity of cancer cellsto a cancer therapy selected from chemotherapy or radiation therapy byadministering to a patient a compound as recited in Embodiment I-1.

Embodiment M-64: The method as recited in Embodiment M-63, wherein thecancer cells are pancreatic cancer cells.

Embodiment M-65: A method for achieving an effect in a patientcomprising the administration of a therapeutically effective amount of acompound as recited in claim 1 to a patient, wherein the effect isincreased sensitivity to chemotherapic agents.

List of Abbreviations

Boc=tert-butyloxycarbonyl;BPin=4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl; Br₂=bromine;Bu=n-butyl; t-Bu=tert-butyl=2,2-dimethylethyl; ° C.=Celsius;CBz=carboxybenzyl; CDCl₃=deuterated chloroform; CD₃CN=deuteratedacetonitrile; DBN=1,5-Diazabicyclo(4.3.0)non-5-ene;DBU=1,8-diazabicyclo(5.4.0)undec-7-ene; DCM=CH₂Cl₂=dichloromethane;DDTT=3-((dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione;DIPEA=iPr₂NEt=diisopropylethylamine; DMAP=4-Dimethylaminopyridine;DMF=dimethylformamide; DMF-d₇=dimethylformamide-d₇; DMSO=dimethylsulfoxide; DMSO-d₆=dimethyl sulfoxide-d₆;DMTr=dimethoxytrityl=(4-methoxyphenyl)₂(phenyl)methyl; D₂O=deuteratedwater; dppf=1,1′-bis(diphenylphosphino)ferrocene; EA=EtOAc=ethylacetate; ES+=electrospray positive ionization; ES−=electrospray negativeionization; Et=ethyl; EtOH=ethanol; h=hour; H=hydrogen; HCl=hydrogenchloride; HCO₂NH₄=ammonium formate; H₂O=water; HPLC=high pressure liquidchromatography, also known as preparative high performance liquidchromatography; int.=intermediate; iPr=isopropyl=2-propyl; M=molar;mCPBA=m-chloroperbenzoic acid; MeCN═CH₃CN=acetonitrile; MeOH=methanol;MHz=megahertz; mL=milliliter; min=minute; MS=mass spectrometry;MsCl=methanesulfonyl chloride; μW=microwave; N₂=nitrogen; NH₃=ammonia;NH₄OH=ammonium hydroxide; NMP=N-Methyl-2-pyrrolidone; ¹H-NMR=protonnuclear magnetic resonance; ³¹P-NMR=phosphorous nuclear magneticresonance; PBS=phosphate buffered saline; PE=petroleum ether;Pin=pinacol=2,3-dimethylbutane-2,3-diol;Pin₂B2=4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane);Piv=pivaloyl=(CH₃)₃C—C(═O)—; PPA=polyphosphoric acid;prep-HPLC=preparative high pressure liquid chromatography, also known aspreparative high performance liquid chromatography; RT=room temperature;NaOH=sodium hydroxide;Pd(dppf)Cl₂=[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride;RuPhos=dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine;THF=tetrahydrofuran; Py=pyridine; SFC=supercritical fluidchromatography; TBSCl=tert-butyldimethylsilyl chloride;TEA=triethylamine; TEAB=tetraethyl ammonium bicarbonate;TMSCl=trimethylsilyl chloride; TFA=trifluoroacetic acid; K₂CO₃=potassiumcarbonate; μL=ul=microliter.

General Synthetic Methods for Preparing Compounds

The following schemes can be used to practice the present disclosure.

A Buchwald coupling reaction with chloro-pyrimidine 101 and asulfoximine gives the substituted pyrimidine compound 102.

One route for preparation of compounds of the present disclosure isdepicted in Scheme II. A Buchwald coupling with intermediate 201 and asulfoximine provides chloropyrimidine 202. A subsequent Suzuki couplingwith a boronic ester or a Stille coupling with a stannane affords thepyrimidine compound 203.

One route for preparation of compounds of the present disclosure isdepicted in Scheme III. A Buchwald coupling with chloropyrimidine 301and an aryl amine, followed by iron mediated reduction or palladiumcatalyzed hydrogenation, provides the amino intermediate 303. Subsequentcyclization with either an orthoester or a carboxylic acid affords thepyrimidine compound 304.

One route for preparation of compounds of the present disclosure isdepicted in Scheme IV. Conversion of chloropyrimidine 401 to stannane402 and subsequent Stille coupling with an aryl bromide affords thepyrimidine compound 403.

One route for preparation of compounds of the present disclosure isdepicted in Scheme V. A Buchwald coupling or a S_(N)Ar addition withchloropyrimidine 501 and an amino-heterocycle affords the pyrimidinecompound 402.

Intermediate A

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 51.0 mmol),Pin₂B₂ (15.5 g, 61.0 mmol), PdCl₂(dppf) (2.0 g, 2.5 mmol) and KOAc (10.0g, 102 mmol) in 1,4-dioxane (200 mL) was degassed with Ar for 5 minutes.The reaction mixture was heated to 80° C. and stirred for 16 h. Themixture was cooled to RT, filtered through CELITE® and concentratedunder reduced pressure. The residue was purified via silica gelchromatography (0-25% EtOAc in hexanes) to afford the title compound(3.8 g, 31% yield) as a white solid.

MS (ES⁺) C₁₃H₁₇BN₂O₂ requires: 244, found: 245 [M+H]⁺.

Intermediate B

(R)-4-(6-chloro-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine

6(R)-4-(2,6-Dichloropyrimidin-4-yl)-3-methylmorpholine To a solution of2,4,6-trichloropyrimidine (12.3 g, 67.3 mmol) and Et₃N (14.2 mL, 101mmol) in EtOH (80 mL) was added (R)-3-methylmorpholine (6.8 g, 67 mmol).The reaction mixture was stirred at RT for 16 h. The mixture wasconcentrated under reduced pressure. The residue was diluted with CH₂Cl₂(200 mL), partitioned with H₂O (150 mL) and the layers were separated.The aqueous layer was extracted with CH₂Cl₂ (3×150 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified via silica gel chromatography(0-5% EtOAc in hexanes) to afford the title compound (11.8 g, 71% yield)as a white solid.

MS (ES+) C₉H₁₁Cl₂N₃O requires: 241, found: 248 [M+H]⁺.

(R)-4-(6-Chloro-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholineA mixture of the product from the previous step (3.0 g, 12 mmol), Int. A(2.8 g, 12 mmol), PdCl₂(dppf) (0.44 g, 0.60 mmol) and Na₂CO₃ (2.6 g, 24mmol) in 1,4-dioxane (60 mL) and water (15 mL) was degassed with Ar for5 minutes. The reaction mixture was heated to 90° C. and stirred for 16h. The reaction mixture was cooled to RT and concentrated under reducedpressure. The residue was purified via silica gel chromatography (0-50%EtOAc in hexanes) to afford the title compound (1.84 g, 46% yield) as ayellow solid.

MS (ES+) C₁₆H₁₆ClN₅O requires: 329, found: 330 [M+H]⁺.

Intermediate C

Iminodimethyl-λ⁶-sulfanone

Benzyl (dimethyl(oxo)-λ⁶-sulfaneylidene)carbamate To a suspension ofDMSO (780 mg, 10.0 mmol), benzyl carbamate (2.3 g, 15 mmol), Rh₂(OAc)₄(110 mg, 0.25 mmol) and MgO (1.6 g, 40 mmol) in CH₂Cl₂ (100 mL) wasadded PhI(OAc)₂ (4.8 g, 15 mmol). The resulting mixture was stirred atRT for 16 h. The reaction mixture was filtered and concentrated underreduced pressure. The residue was purified via flash chromatography(0-90% EtOAc in petroleum ether) to afford the title compound (900 mg,40% yield) as a white solid.

MS (ES⁺) C₁₀H₁₃NO₃S requires: 227, found: 228 [M+H]⁺.

Iminodimethyl-λ⁶-sulfanone The product from the previous step (600 mg,2.6 mmol) and Pd/C (243 mg, 2.6 mmol) were suspended in MeOH (20 mL).The mixture was stirred under an atmosphere of H₂ at 1 atm for 16 h. Thereaction mixture was purged with N₂, filtered through CELITE® and thefilter pad was washed with MeOH (10 mL). The mixture was concentratedunder reduced pressure to afford the title compound (205 mg, 85% yield)as a colorless oil.

MS (ES⁺) C₂H₇NOS requires: 93, found 94 [M+H]⁺.

Intermediate D

(R)-((2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone

(R)-((2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A reaction vial was charged with(R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized asdescribed for Int. B, step 1) (500 mg, 2.02 mmol), Int. C (225 mg, 2.42mmol) and dioxane (10 mL) and the mixture was degassed with N₂ for 30seconds. Cs₂CO₃ (1.97 g, 6.05 mmol), Pd₂dba₃ (185 mg, 0.202 mmol) andxantphos (233 mg, 0.403 mmol) were added and the mixture was degassedwith N₂ for 30 seconds. The vial was sealed and heated at 85° C. for 16h. The mixture was cooled to RT, filtered through CELITE® andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (0-10% MeOH in EtOAc) to afford(R)-((2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone(362 mg, 59% yield) as a pale yellow solid and(R)-((4-chloro-6-(3-methylmorpholino)pyrimidin-2-yl)imino)dimethyl-λ⁶-sulfanone(222 mg, 36% yield) as a pale yellow solid.

¹H NMR (600 MHz, CDCl₃) δ 5.73 (s, 1H), 4.21-4.15 (m, 1H), 3.96 (dd,J=11.5, 3.7 Hz, 1H), 3.91 (d, J=13.0 Hz, 1H), 3.74 (d, J=11.5 Hz, 1H),3.67 (dd, J=11.5, 3.2 Hz, 1H), 3.52 (td, J=11.9, 3.1 Hz, 1H), 3.37 (d,J=3.1 Hz, 6H), 3.19 (td, J=12.8, 3.9 Hz, 1H), 1.26 (d, J=6.8 Hz, 3H); MS(ES⁺) C₁₁H₁₇ClN₄O₂S requires: 304, found: 305 [M+H]⁺.

Intermediate E

Cyclopropyl(imino)(methyl)-λ⁶-sulfanone Step 1

(Methylsulfinyl)cyclopropane: To a solution of1-bromo-4-(methylsulfinyl)benzene (10.5 g, 48.0 mmol) in THF (100 mL)was added cyclopropylmagnesium bromide (1M, 72 mL, 72 mmol) at 0° C.slowly. The mixture was stirred at 0° C. for 1.5 h. Saturated aqueousNH₄Cl was added (200 mL), the layers were separated and the aqueouslayer was extracted with CH₂Cl₂ (5×150 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified via flash chromatography (50-100%EtOAc in petroleum ether) to afford the title compound (3.2 g, 64%yield) as a yellow oil.

MS (ES⁺) C₄H₈OS requires: 104, found 105 [M+H]⁺.

Step 2

Cyclopropyl(imino)(methyl)-λ⁶-sulfanone: To the solution of the productfrom the previous step (22 g, 0.21 mol) and PhI(OAc)₂ (204 g, 0.64 mol)in MeOH (100 mL) at 0° C. was added NH₃ (120 mL, 0.84 mol, 7 N in MeOH)dropwise. The resulting mixture was allowed to warm to RT and stirredfor 2 hours. The reaction mixture was concentrated under reducedpressure. The residue was purified via flash chromatography (15% EtOAcin petroleum ether, then with 2% MeOH in CH₂Cl₂) to afford the titlecompound (20 g, 79%) as a yellow oil: ¹H NMR (400 MHz, CDCl3) δ 3.06 (s,3H), 2.58 (tt, J=7.9, 4.8 Hz, 1H), 1.26-1.19 (m, 1H), 1.19-1.12 (m, 1H),1.05 (dt, J=11.1, 4.5 Hz, 2H).

Intermediate F

Imino(methyl)(oxetan-3-yl)-λ⁶-sulfanone Step 1

3-(methylsulfinyl)oxetane: To a solution of 3-iodooxetane (6.0 g, 32.6mmol) in DMF (60 mL) was added CH₃SNa (2.28 g, 32.6 mmol) under N₂. Thereaction mixture was stirred at RT for 1 h. EtOAc (120 mL) and water (80mL) were added, the layers were separated and the organic layer waswashed with brine (80 mL), dried over MgSO₄ and filtered. The solutionof EtOAc was added MeOH (60 mL), water (60 mL) and NaIO₄ (6.2 g, 29.3mmol) and the reaction mixture was stirred at RT for 16 h. The mixturewas filtered and concentrated under reduced pressure. The residue waspurified via flash chromatography (50% EtOAc in petroleum ether to 10%MeOH in CH₂Cl₂) to afford the title compound (3.5 g, 90% yield) as paleyellow oil.

MS (ES⁺) C₄H₈O₂S requires: 120, found 121 [M+H]⁺.

Step 2

Benzyl (methyl(oxetan-3-yl)(oxo)-λ⁶-sulfaneylidene)carbamate: To asolution of the product from the previous step (3.5 g, 29 mmol) inCH₂Cl₂ (260 mL) were added benzyl carbamate (6.58 g, 43.6 mmol),Rh₂(OAc)₄ (383 mg, 0.873 mmol), PhI(OAc)₂ (14.0 g, 43.6 mmol) and MgO(4.7 g, 116 mmol) and the mixture was stirred at RT under an atmosphereof N₂ for 16 h. The reaction mixture was filtered through CELITE® andconcentrated under reduced pressure. The residue was purified via flashchromatography (20-50% EtOAc in petroleum ether) to afford the titlecompound (4.1 g, 52% yield) as pale yellow oil.

MS (ES⁺) C₁₂H₁₅NO₄S requires: 269, found 270 [M+H]⁺.

Step 3

Imino(methyl)(oxetan-3-yl)-λ⁶-sulfanone: To a solution of the productfrom the previous step (4.1 g, 15 mmol) in MeOH (60 mL) was added Pd/C(4.1 g) under N₂. The atmosphere was removed and purged with H₂ (3×).The mixture was heated to 50° C. and stirred for 3 h under a H₂atmosphere. The mixture was cooled to RT, filtered through CELITE® andconcentrated under reduced pressure to afford the title compound (1.7 g,83% yield) as pale yellow oil.

MS (ES⁺) C₄H₉NO₂S requires: 135, found 136 [M+H]⁺.

Intermediate G

2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridineStep 1

4-Bromo-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine: To a solution of4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.0 g, 2.9 mmol) in THF (30mL) at −78° C. was added LDA (2.9 mL, 2 M, in THF) and the mixture wasstirred for 1 h at −78° C. under an atmosphere of Ar. Mel (4.0 g, 29mmol) was added and the mixture was allowed to warm to RT and stirredfor 3 h. Saturated aqueous NH₄Cl (50 mL) was added and the aqueous layerwas extracted with EtOAc (3×50 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by reverse phase preparative HPLC (Mobile phase:A=10 mM NH₄HCO₃/H₂O, B=MeCN; Gradient: B=65-95%; 18 min; Column: WelchXB-C18, 10 μm, 21.2×250 mm) to afford the title compound (420 mg, 40%yield) as a white solid.

MS (ES⁺) C₁₅H₁₃BrN₂O₂S requires: 364, found 365 [M+H]⁺.

Step 2

2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine:A reaction vial was charged with the product from the previous reaction(410 mg, 1.13 mmol), Pin₂B₂ (345 mg, 1.3 mmol), KOAc (277 mg, 2.8 mmol)and Pd(dppf)Cl₂ (82 mg, 0.11 mmol) in dioxane (5 mL). The mixture wasdegassed by bubbling Ar for 1 min. The mixture was heated at 80° C. andstirred for 5 h. The mixture was cooled to RT, filtered through CELITE®and concentrated under reduced pressure. the residue was purified viaflash chromatography (20% EtOAc in petroleum ether) to afford the titlecompound (350 mg, 75% yield) as a white solid.

MS (ES⁺) C₂₁H₂₅BN₂O₄S requires 412, found 331 [M-81]⁺.

Intermediate H

4-Bromo-6-ethoxy-1H-pyrrolo[2,3-b]pyridine Step 1

4-Bromo-6-ethoxy-1H-pyrrolo[2,3-b]pyridine: A mixture of4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (426 mg, 2.0 mmol) anddimethyl sulfate (303 mg, 2.4 mmol) in CH₃CN (10 mL) was heated to 70°C. for 24 h. The reaction mixture was cooled to RT, sodium ethanolate(40 mg, 6.0 mmol) was added and the mixture was heated to 70° C. for 24h. The reaction mixture was cooled to RT, neutralized with AcOH to pH=7and then concentrated under reduced pressure. The residue was dissolvedin CH₂Cl₂ (50 mL), washed with aq. sat. NaHCO₃(20 mL) and brine (15 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified via silica gel chromatography (0-20% EtOAc inpetroleum ether) to afford the title compound (151 mg, 31% yield) as awhite solid.

MS (ES⁺) C₉H₉BrN₂O requires: 240, found: 241 [M+H]⁺.

Intermediate I

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridineStep 1

4-Bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridine: To a solution of4-bromo-1H-pyrrolo[2,3-c]pyridine (300 mg, 1.5 mmol) in DMF (10 mL) at0° C. was added NaH (92 mg, 2.25 mmol, 60%) and the reaction mixture wasstirred at 0° C. for 2 h. The reaction mixture was allowed to warm toRT, TsCl (429 mg, 2.25 mmol) was added and the mixture was heated to 60°C. and stirred for an additional 2 h. H₂O (10 mL) was added, the layerswere separated and the aqueous layer was extracted with EtOAc (3×15 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography (0-20% EtOAc in petroleum ether) to afford the titlecompound (300 mg, 57% yield) as a white solid.

MS (ES⁺) C₁₄H₁₁BrN₂O₂S requires 350, found 351 [M-81]⁺.

Step 2

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridine:A mixture of the product from the previous step (300 mg, 0.86 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (254 mg, 1.0mmol), Pd(dppf)Cl₂ (63 mg, 0.086 mmol) and KOAc (169 mg, 1.72 mmol) indioxane (10 mL) was degassed with Ar and the reaction mixture was heatedat 120° C. for 4 h. The reaction mixture was cooled to RT, filteredthrough CELITE® and concentrated under reduced pressure. The residue waspurified by flash chromatography (10-60% EtOAc in petroleum ether) toafford the title compound (100 mg, 29% yield) as a white solid.

MS (ES⁺) C₂₀H₂₃BN₂O₄S requires 398, found 399 [M+H]⁺.

Intermediate J

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2,3-diamine

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2,3-diamine: Toa solution of 4-bromopyridine-2,3-diamine (200 mg, 1.07 mmol), KOAc (262mg, 2.67 mmol) and Pin₂B₂ (544 mg, 2.14 mmol) in dioxane (10 mL) wasadded Pd(dppf)Cl₂ (63 mg, 0.086 mmol) and the mixture was stirred at 80°C. for 16 h under an atmosphere of Ar. The reaction mixture was cooledto RT, filtered through CELITE® and concentrated under reduced pressure.The residue was taken up in petroleum ether (20 mL) and stirred for 10minutes, filtered and concentrated to afford the title compound (>250mg, assumed quantitative) as a brown solid.

MS (ES⁺) C₁₁H₁₈BN₃O₂ requires: 235, found 154 [M-81]⁺.

Intermediate K

6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine:A suspension of 4-bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine (100 mg,0.432 mmol), Pin₂B₂ (121 mg, 0.475 mmol) and KOAc (127 mg, 1.30 mmol) indioxane (2160 μL) was degassed with N₂ for 1 minute. PdCl₂(dppf)-CH₂Cl₂(17 mg, 0.022 mmol) was added and the mixture was degassed with N₂ foran additional 1 minute. The reaction mixture was heated to 100° C. andstirred for 12 h. The mixture was cooled to RT, filtered through CELITE®and concentrated under reduced pressure to afford the title compound(assumed quantitative) as a brown solid.

MS (ES⁺) C₁₃H₁₆BCN₂O₂ requires: 278, found: 279 [M+H]⁺.

Intermediate L

N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine:To a solution of 4-bromo-N-methylpyridin-2-amine (85 mg, 0.45 mmol),KOAc (132 mg, 1.35 mmol) and Pin₂B₂(220 mg, 0.9 mmol) in dioxane (15 mL)was added Pd(dppf)Cl₂ (15 mg, 0.02 mmol) and the mixture was heated at90° C. and stirred for 16 h under an atmosphere of N₂. The reactionmixture was cooled to RT, EtOAc (50 mL) was added and the mixture wasstirred for 5 min. The mixture was filtered through CELITE® andconcentrated under reduced pressure to give the title compound (100 mg)as a brown solid, which was used without further purification.

MS (ES⁺) C₁₂H₁₉BN₂O₂ requires: 234, found: 153 [M-81]⁺.

Intermediate M

7-Iodo-3-trityl-3H-imidazo[4,5-b]pyridine Step 1

7-Iodo-3H-imidazo[4,5-b]pyridine hydroiodide: A mixture of7-chloro-3H-imidazo[4,5-b]pyridine (735 mg, 4.80 mmol) in aq. HI (12 mL)was heated at 80° C. and stirred for 16 h. The mixture was cooled to RT,the solid was collected by vacuum filtration and dried under vacuum toafford the title compound (1.5 g, 84% yield) as a yellow solid.

MS (ES⁺) C₆H₄IN₃ requires: 245, found: 246 [M+H]⁺.

Step 2

7-Iodo-3-trityl-3H-imidazo[4,5-b]pyridine: To a solution of the productfrom the previous step (735 mg, 1.97 mmol) in DMF (8 mL) at 5° C. wasadded NaH (158 mg, 3.94 mmol, 60% in mineral oil) and the resultingmixture was stirred at this temperature for 2 h. The the reactionmixture was added a solution of trityl chloride (822 mg, 2.96 mmol) inDMF (2 mL) dropwise and the resulting mixture was stirred an additional2 h. The reaction mixture was concentrated under reduced pressure. Theresidue was purified via silica gel chromatography (10-25% EtOAc inhexanes) to afford the title compound (620 mg, 65% yield) as a whitesolid.

¹H NMR (500 MHz, DMSO-d₆) δ 8.23 (s, 1H), 7.71 (d, J=5.0 Hz, 1H), 7.64(d, J=5.0 Hz, 1H), 7.39-7.25 (m, 9H), 7.20 (d, J=7.2 Hz, 6H).

Intermediate N

(R)-(4-benzylmorpholin-3-yl)methanol Step 1

Benzoyl-D-serine: To a stirred solution of(R)-2-amino-3-hydroxypropanoic acid (50 g, 476 mmol), benzoyl chloride(66.64 g, 476 mmol) and K₂CO₃ (131.6 g, 952 mmol) in H₂O (500 mL) at 25°C. for 16 h. The reaction mixture was adjusted to pH=3-4 with 1 N HCland the aqueous layer was extracted with EtOAc (800 mL). The organiclayer was washed with brine (2×500 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound (35.8g, 40% yield) as a white solid.

MS (ES⁺) C₁₀H₁₁NO₄ requires: 209, found: 210 [M+H]⁺.

Step 2

N-benzoyl-O-benzyl-D-serine: To suspension of NaH (33.06 g, 1378 mmol)in DMF (300 mL) at 0° C. under an atmosphere of N₂ was added the productfrom the previous step (96 g, 459 mmol) in DMF (300 mL) and theresulting mixture was stirred for 1 h at 0° C. Benzyl bromide (54.54 mL,459.2 mmol) was added and the mixture was allowed to warm to RT andstirred for 5 h. The reaction mixture was poured into ice water, thelayers were separated and the aqueous phase was extracted with Et₂O(1200 mL). The aqueous phase was acidified with 4 N HCl and extractedwith CH₂Cl₂ (1200 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure to afford the title compound(126 g, 69% yield), which was used without further purification.

MS (ES⁺) C₁₇H₁₇NO₄ requires: 299, found: 300 [M+H]⁺.

Step 3

(S)-2-(benzylamino)-3-(benzyloxy)propan-1-ol: To a solution of theproduct from the previous step (50 g, 167 mmol) in THF (500 mL) wasadded BH₃-THF (1 M in THF, 1.8 L, 1672 mmol) at 0° C. under anatmosphere of N₂ and the resulting mixture was warmed to RT and stirredfor 16 h. MeOH (1 L) was added dropwise and the mixture was concentratedunder reduced pressure. MeOH (1.5 L) and 1 N aq. NaOH (2.225 L) wasadded to the residue, and the mixture was heated at reflux for 3 h. Themixture was cooled to RT and concentrated under reduced pressure. Theresidue was partitioned between H₂O (2 L) and EtOAc (2 L) and the layerswere separated. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound (40 g,88% yield) as colorless oil, which was used without furtherpurification.

MS (ES⁺) C₁₇H₂₁NO₂ requires: 271, found: 272 [M+H]⁺.

Step 4

(R)-4-benzyl-5-((benzyloxy)methyl)morpholin-3-one: To a solution of theproduct from the previous step (10 g, 37 mmol) in CH₂Cl₂ (100 mL) at 0°C. was added triethylamine (5.91 mL, 42.4 mmol) and chloroacetylchloride (3.35 ml, 42.4 mmol) and the resulting mixture was stirred for1 h at 0° C. The reaction mixture was partitioned between 1N HCl (100mL) and CH₂Cl₂ (100 mL) and the layers were separated. The organic layerwas washed with brine (150 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was dissolved into2-propanol (150 mL), KOH (4.14 g, 73.8 mmol) was added and the mixturewas stirred for 15 hours at RT. The mixture was concentrated underreduced pressure, the residue was partitioned between water (100 mL) andEtOAc (100 mL) and the layers were separated. The organic layer waswashed with brine (100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (50% EtOAc in hexanes) to afford the title compound (7.46g, 65% yield) as a yellowish oil.

MS (ES⁺) C₁₉H₂₁NO₃ requires: 311, found: 312 [M+H]⁺.

Step 5

(R)-4-benzyl-5-(hydroxymethyl)morpholin-3-one: To a suspension of theproduct from the previous step (25 g, 80 mmol) and 10% palladium onactivated carbon (13 g, 8 mmol) in EtOH (150 mL) and acetic acid (50 mL)was stirred at 40° C. under an atmosphere of H₂ at 1 atm for 16 h. Themixture was cooled to RT, purged with N₂, filtered through CELITE® andconcentrated under reduced pressure. The residue was concentrated fromtoluene (2×100 mL) to afford the title compound (32 g, assumedquantitative), which was used without further purification.

MS (ES⁺) C₁₂H₁₅NO₃ requires: 221, found: 222 [M+H]⁺.

Step 6

(R)-(4-benzylmorpholin-3-yl)methanol: To a solution of the product fromthe previous step (24 g, 108.55 mmol) in THF (50 mL) under an atmosphereof N₂ was added borane-methyl sulfide complex (1.0 M in THF, 40 mL) andthe resulting was heated at 80° C. for 16 h. The mixture was cooled toRT, MeOH (60 mL) was added dropwise and concentrated under reducedpressure. The residue was partitioned between MeOH (40 mL) and 1 N aq.NaOH (40 mL) and the layers were separated. The organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (5-10% EtOAc inhexanes) to afford the title compound (21.8 g, 97% yield) as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.37-7.18 (m, 5H), 4.59 (t, J=5.3 Hz, 1H),4.04 (d, J=13.6 Hz, 1H), 3.79-3.64 (m, 2H), 3.58 (dt, J=11.0, 3.4 Hz,1H), 3.45-3.35 (m, 3H), 3.27 (d, J=13.6 Hz, 1H), 2.56-2.44 (m, 2H), 2.11(ddd, J=12.1, 9.1, 3.2 Hz, 1H); MS (ES⁺) C₁₂H₁₇NO₂ requires: 207, found:208 [M+H]⁺.

Intermediate 0

(S)-3-(Fluoromethyl)morpholine Step 1

(S)-4-benzyl-3-(fluoromethyl)morpholine: To a solution of Int. N (6.81g, 3.28 mmol) in CH₂Cl₂ (50 mL) at 0° C. was added diethylaminosulfurtrifluoride (6.26 mL, 4.9 mmol) dropwise and the resulting mixture wasstirred at RT for 3 h. The reaction mixture was added dropwise toice-water, aq. sat. NaHCO₃was added to adjust to pH=8, and the aqueouslayer was extracted with CH₂Cl₂ (3×50 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography (90%EtOAc in hexanes) to afford the title compound (5.18 g, 70% yield) as ayellow liquid.

MS (ES⁺) C₁₂H₁₆FNO requires: 209, found: 210 [M+H]⁺.

Step 2

(S)-3-(Fluoromethyl)morpholine: A solution of the product from theprevious step (5.18 g, 24.7 mmol) in DCE (50 mL) was added 1-chloroethylchloroformate (26.7 mL, 247 mmol) and the resulting mixture was heatedat 80° C. and stirred for 16 h. The resulting mixture was cooled to RT,MeOH was added until no bubbles were observed, DCE was removed underreduced pressure and the residue was heated at reflux for 1 h. Themixture was cooled to RT, concentrated under pressure and n-heptane wasadded and the mixture was concentrated under reduced pressure (2×50 mL).The residue was triturated with EtOAc to afford the title compound (25g, 60% yield) as a white solid.

MS (ES⁺) C₅H₁₀FNO requires: 119, found: 120 [M+H]⁺.

Intermediate P

5-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineStep 1

5-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine:A sealed tube charged with 4-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine(100 mg, 0.465 mmol), KOAc (137 mg, 1.40 mmol), Pin₂B₂ (142 mg, 0.558mmol), PdCl₂(dppf)-CH₂Cl₂ (19 mg, 0.023 mmol) followed by dioxane (3.1mL). The mixture was degassed by bubbling with stream of N₂ for 1minute. The tube was sealed and the reaction mixture was heated for at90° C. for 18 h. The reaction mixture was cooled to RT, filtered throughCELITE®, washed with EtOAc (5 mL), and concentrated under reducedpressure. The residue was purified via silica gel chromatography (0-10%MeOH in CH₂Cl₂) to afford the title compound (112 mg, 46% yield) as apale yellow solid.

MS (ES⁺) C₁₃H₁₆BFN₂O₂ requires: 262, found: 181 [M-81]⁺.

Intermediate Q

((2-Chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone

((2-Chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone:To the mixture of Int. E (47 g, 0.19 mol),(R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized asdescribed for Int. B, step 1) (22 g, 0.19 mol) in dioxane (750 mL) wereadded Pd₂(dba)₃ (8.6 g, 9.4 mmol), XantPhos (5.5 g, 9.4 mmol) and Cs₂CO₃(184 g, 0.57 mol). The reaction mixture was degassed with N₂ for 1minute and heated to 80° C. and stirred under an atmosphere of N₂ for 6h. The mixture was cooled to RT, filtered through CELITE® andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (0-100% EtOAc in hexanes) to afford the titlecompound (26 g, 41% yield) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 5.86 (s, 1H), 4.22 (d, J=5.3 Hz, 1H),3.92-3.80 (m, 2H), 3.66 (d, J=11.4 Hz, 1H), 3.54 (dd, J=11.5, 2.9 Hz,1H), 3.45 (s, 3H), 3.39 (td, J=11.9, 3.0 Hz, 1H), 3.12-2.93 (m, 2H),1.26-1.19 (m, 1H), 1.17-1.04 (m, 6H). MS (ES⁺) C₁₃H₉CN₄O₂S requires:330, found: 331 [M+H]⁺.

Intermediate R

Tert-butyl 1-imino-1λ⁶-thiomorpholine-4-carboxylate 1-oxide Step 1

tert-Butyl1-(((benzyloxy)carbonyl)imino)-1λ⁶-thiomorpholine-4-carboxylate 1-oxide:To a suspension of tert-butyl thiomorpholine-4-carboxylate 1-oxide (2.0g, 9.1 mmol), benzyl carbamate (2.10 g, 13.7 mmol), MgO (1.5 g, 36 mmol)and Rh₂(OAc)₄ (0.1 g, 0.23 mmol) in CH₂Cl₂ (20 mL) was added PhI(OAc)₂(4.40 g, 13.7 mmol) and the resulting mixture was stirred at RT for 18h. The reaction mixture was filtered through CELITE® and concentratedunder reduced pressure. The residue was purified via silica gelchromatography (0-40% EtOAc in petroleum ether) to afford the titlecompound (2.4 g, 36% yield) as a white solid.

MS (ES⁺) C₁₇H₂₄N₂O₅S requires: 368, found: 369 [M+H]⁺.

Step 2

tert-Butyl 1-imino-1)⁶-thiomorpholine-4-carboxylate 1-oxide: Asuspension of the product from the previous step (1.0 g, 2.7 mmol) and10% Pd/C (250 mg, 0.235 mmol) in MeOH (20 mL) was stirred under H₂ for16 h. The reaction mixture was filtered through CELITE® and concentratedunder reduced pressure to afford the title compound (500 mg, 79% yield)as colorless oil. The crude product was used for subsequent step withoutfurther purification.

MS (ES⁺) C₉H₁₈N₂O₃S requires: 234, found: 235 [M+H]⁺.

Intermediate S

6-Methoxy-N-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amineStep 1

6-Chloro-4-iodo-N-(4-methoxybenzyl)pyridin-2-amine: A microwave vial wascharged with 2,6-dichloro-4-iodopyridine (10 g, 36 mmol),4-methoxybenzylamine (23.4 mL, 179 mmol) and ethanol (20 mL). The vialwas sealed and the reaction mixture was heated to 150° C. in a microwavereactor for 4 h. The mixture was cooled to RT, poured into water (20 mL)and the aqueous layer was extracted with EtOAc (3×20 mL). The combinedorganic fractions were dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified via silica gelchromatography (0-20% EtOAc in hexanes) to afford the title compound(9.24 g, 69% yield) as a white solid.

MS (ES⁺) C₁₃H₁₂C₁IN₂O requires: 374, found: 375 [M+H]⁺.

Step 2

4-Iodo-6-methoxy-N-(4-methoxybenzyl)pyridin-2-amine: To a suspension ofthe product from the previous step (1.0 g, 2.67 mmol) in dioxane (5.3mL) at 0° C. was added sodium methoxide (1.8 mL, 8.0 mmol, 25% in MeOH)and the resulting mixture was stirred at 100° C. for 16 h. 1 N HCl (5mL) was added, the layers were separated and the aqueous layer wasextracted with EtOAc (3×30 mL). The combined organic layers were washedwith brine (10 mL), dried over MgSO₄, filtered through CELITE® andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (0-20% EtOAc in hexanes) to afford the title compound(844 mg, 85% yield) as a colorless liquid.

MS (ES⁺) C₁₄H₁₅IN₂O₂ requires: 370, found: 371 [M+H]⁺.

Step 3

6-Methoxy-N-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine:A suspension of the product from the previous step (900 mg, 2.43 mmol),Pin₂B₂ (741 mg, 2.92 mmol) and KOAc (716 mg, 7.29 mmol) in dioxane (12.2mL) was degassed with N₂ for 1 minute. PdCl₂(dppf)-CH₂Cl2 (99 mg, 0.12mmol) was added and the mixture was degassed with N₂ for an additional 1minute. The reaction mixture was heated at 120° C. in a microwavereactor for 10 h. The mixture was cooled to RT, filtered through CELITE®and concentrated under reduced pressure. The residue was purified viasilica gel chromatography (0-60% EtOAc in hexanes) to afford the titlecompound (860 mg, 72% yield) as a pale yellow liquid.

MS (ES⁺) C₂₀H₂₇BN₂O₄ requires: 370, found: 289 [M-81]⁺.

Intermediate T

(R)-4-(6-chloro-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine

(R)-4-(6-chloro-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)-3-methylmorpholine:To a solution of (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine(synthesized as described for Int. B, step 1) (467 mg, 1.88 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(900 mg, 2.26 mmol) in dioxane (7.1 mL) and water (2.4 μL) were addedNa₂CO₃ (439 mg, 4.14 mmol) and PdCl₂(dppf)-CH₂Cl2 (77 mg, 0.094 mmol)and the resulting mixture was degassed with N₂ for 1 minute and stirredat 110° C. for 4 h. The reaction mixture was cooled to RT, partitionedbetween EtOAc (5 mL) and H₂O (2 mL), the layers were separated and theaqueous layer was extracted with EtOAc (3×5 mL). The combined organiclayers were washed with brine (2 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (0-60% EtOAc in hexanes) to afford the title compound(300 mg, 33% yield) as an off-white solid.

¹H NMR (600 MHz, CDCl₃) δ 8.52 (d, J=5.3 Hz, 1H), 8.06 (t, J=7.1 Hz,3H), 7.83 (d, J=4.0 Hz, 1H), 7.48 (d, J=3.9 Hz, 1H), 7.26 (d, J=1.5 Hz,2H), 6.46 (s, 1H), 4.40 (s, 1H), 4.07 (dd, J=11.4, 3.5 Hz, 2H), 3.85 (d,J=11.6 Hz, 1H), 3.75 (dd, J=11.7, 3.1 Hz, 1H), 3.60 (td, J=11.9, 2.8 Hz,1H), 3.37 (td, J=12.8, 4.0 Hz, 1H), 2.36 (s, 3H), 1.37 (d, J=6.9 Hz,3H); MS (ES⁺) C₂₃H₂₂ClN₅O₃S: 483, found: 484 [M+H]⁺.

Intermediate U

4-Bromo-2-cyclopropyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine

4-Bromo-2-cyclopropyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine: A mixture of4-bromo-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.3 g, 0.63 mmol),cyclopropylboronic acid (0.054 g, 0.63 mmol), Pd(PPh₃)₄ (73 mg, 0.063mmol), Na₂CO₃ (134 mg, 1.26 mmol), dioxane (10 mL) and H₂O (2 mL) waspurged with Ar₂, sealed and heated at 130° C. for 3 h in a microwavereactor. The reaction mixture was cooled to RT, filtered through CELITE®and concentrated under reduced pressure. The residue was purified viasilica gel chromatography (0-10% EtOAc in hexanes) to afford the titlecompound (30 mg, 12% yield) as a white solid.

MS (ES⁺) C₁₇H₁₅BrN₂O₂S requires: 390 found: 391 [M+H]⁺.

Intermediate V

(R)-dimethyl((6-(3-methylmorpholino)-2-(tributylstannyl)pyrimidin-4-yl)imino)-λ⁶-sulfanone

(R)-dimethyl((6-(3-methylmorpholino)-2-(tributylstannyl)pyrimidin-4-yl)imino)-λ⁶-sulfanone,intermediate 5: To a flame dried round bottom flask, under an atmosphereof Ar, was added anhydrous THF (2 mL) and di-isopropylamine (310 μL, 2.2mmol). The solution was cooled to −10° C. and n-BuLi (2.5 M in hexanes,0.84 mL, 2.1 mmol) was added dropwise and the resulting mixture waswarmed to 0° C. over 5 minutes. A solution of Bu₃SnH (538 μL, 2.0 mmol)in THF (2.0 mL) was added dropwise and the resulting mixture was stirredat 0° C. for 20 minutes, and then cooled to −78° C. A solution of Int. D(610 mg, 2.0 mmol) in THF (2.0 mL) was added to the mixture at −78° C.and the resulting mixture was stirred at −78° C. for 1 h. Water (10 ml)was added to the mixture, the layers were separated and the aqueouslayer was extracted with EtOAc (3×5 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified via silica gel chromatography (20 to100% EtOAc in hexanes) to afford the title compound (350 mg, 31% yield)as a colorless oil.

MS (ES⁺) C₂₃H₄₄N₄O₂SSn requires: 560, found: 561 [M+H]⁺.

Intermediate W

(S)-3-(difluoromethyl)morpholine hydrochloride Step 1

(S)-4-benzylmorpholine-3-carbaldehyde: To a solution of DMSO (20.6 mL,290 mmol) in CH₂Cl₂ (100 mL) at −78° C. was added a solution of oxalylchloride (12.2 mL, 145 mmol) in CH₂Cl₂ (50 mL) dropwise and theresulting mixture was stirred was at −78° C. for 15 minutes. A solutionof Int. N (10 g, 48 mmol) in CH₂Cl₂ (50 mL) was added over 30 min. andthe resulting mixture was warmed to RT and stirred for 30 min. To thereaction mixture was added sat. aq. NaHCO₃(200 mL) and the layers wereseparated. The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound (9.9 g,99% yield), which was used immediately without further purification.

MS (ES⁺) C₁₂H₁₅NO₂ requires: 205 found: 206 [M+H]⁺.

Step 2

(S)-4-benzyl-3-(difluoromethyl)morpholine: To a solution of the productfrom the previous step (9.9 g, 48.267 mmol) in CH₂Cl₂ (100 mL) at 0° C.was added DAST (19.14 mL, 44.8 mmol) was added dropwise whilemaintaining a temperature of 0-5° C. and the resulting reaction mixturewas warmed to RT and stirred for 16 hours. To the reaction mixture wasadded sat. aq. NaHCO₃(50 mL) and the layers were separated. The organiclayer was washed with water (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (hexanes) to afford the title compound (5 g, 45.45%yield) as a yellowish oil.

MS (ES⁺) C₁₂H₁₅F₂NO requires: 227 found: 228 [M+H]⁺.

Step 3

(S)-3-(difluoromethyl)morpholine hydrochloride: To a solution of theproduct from the previous step (2.0 g, 8.806 mmol) in DCE (10 mL) wasadded 1-chloroethyl chloroformate (9.44 mL, 88.1 mmol) and the resultingmixture was heated at 80° C. and stirred for 16 h. The resulting mixturewas cooled to RT, MeOH was added until no bubbles were observed, DCE wasremoved under reduced pressure and the residue was heated at reflux for1 h. The mixture was cooled to RT, concentrated under pressure and2-propanol was added and the mixture was concentrated under reducedpressure (2×10 mL). The residue was triturated with EtOAc to afford thetitle compound (1.9 g, quantitative yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 6.42 (td, J=53.7, 3.9 Hz, 1H), 4.04 (dd,J=12.3, 3.5 Hz, 1H), 4.00-3.83 (m, 2H), 3.82-3.60 (m, 2H), 3.25 (dt,J=12.9, 2.7 Hz, 1H), 3.20-3.06 (m, 1H); MS (ES⁺) CH₉F₂NO requires: 137found: 138 [M+H]⁺.

Intermediate X

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole: Amixture of 4-bromo-1H-benzo[d]imidazole (0.5 g, 2.5 mmol), Pin₂B₂ (0.77g, 3.1 mmol), PdCl₂(dppf) (93 mg, 0.13 mmol) and KOAc (0.5 g, 5.1 mmol)in dioxane (20 mL) was degassed with N₂ for 1 min. and the resultingmixture was heated at 90° C. and stirred for 16 h. The reaction mixturewas cooled to RT, filtered through CELITE® and concentrated underreduced pressure to afford the title compound (0.6 g, assumedquantitative) as a black solid, which was directly used for the nextstep without further purification.

MS (ES⁺) C₁₃H₁₇BN₂O₂ requires: 244 found: 163 [M-81]⁺.

Intermediate Y

6-Chloro-N-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine

6-Chloro-N-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine:A sealed tube was charged with6-chloro-4-iodo-N-(4-methoxybenzyl)pyridin-2-amine (synthesized asdescribed for Int. S, step 1) (500 mg, 1.24 mmol), KOAc (365 mg, 3.72mmol), Pin₂B₂ (378 mg, 1.49 mmol), PdCl₂(dppf)-CH₂Cl₂ (0.051 g, 0.062mmol) and dioxane (8.28 mL) and the resulting mixture was degassed withN₂ for 1 minute. The reaction tube was sealed and the reaction mixturewas heated at 90° C. for 18 h. The reaction mixture was cooled to RT,filtered through CELITE®, washed with EtOAc and concentrated underreduced pressure. The residue was purified via silica gel chromatography(0-50% EtOAc in hexanes) to afford the title compound (525 mg, 56%yield) as an orange liquid.

MS (ES⁺) C₁₉H₂₄BCN₂O₃ requires: 374, found: 293 [M-81]⁺.

Intermediate Z

4-Bromo-6-(2,2,2-trifluoroethoxy)-1H-pyrrolo[2,3-b]pyridine

4-Bromo-6-(2,2,2-trifluoroethoxy)-1H-pyrrolo[2,3-b]pyridine: A solutionof 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (1.73 g, 8.13 mmol) anddimethyl sulfate (1.23 g, 9.75 mmol) in CH₃CN (50 mL) was heated to 70°C. for 24 h. The reaction mixture was cooled to RT. To a suspension ofmixture of NaH (6.24 g, 156 mmol, 60% in mineral oil) in CH₃CN (50 mL)at 0° C. was added 2,2,2-trifluoroethanol (5.2 g, 52 mmol) and theresulting mixture was stirred at 0° C. for 30 minutes. The reactionmixture was then added to the mixture prepared above and the resultingmixture was stirred at 70° C. for 16 h. The mixture was cooled to RT andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (0-67% EtOAc in petroleum ether; then 0-40% acetonein petroleum ether) to afford the title compound (450 mg, 19% yield) asa white solid.

MS (ES⁺) C₉H₆BrF₃N₂O requires: 294, 296, found: 295, 297[M+H]⁺.

Intermediate AA

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]-pyridine-2-carbonitrileStep 1

4-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile: A microwavevial was charged with 4-bromo-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine(200 mg, 0.42 mmol), Zn(CN)₂ (24 mg, 0.21 mmol), Pd(PPh₃)₄ (24 mg, 0.021mmol) and DMF (5 mL). The vial was sealed and the reaction mixture washeated at 150° C. in a microwave reactor for 30 minutes. The reactionmixture was cooled to RT, filtered through CELITE® and concentratedunder reduced pressure. The residue was purified by reverse phasepreparative HPLC (Mobile phase: A=10 mM NH₄HCO₃/H₂O, B=MeCN; Gradient:B=50-80%; 18 min; Column: Welch XB-C18, 10 μm, 21.2×250 mm) to affordthe title compound (20 mg, 12% yield) as a white solid.

MS (ES⁺) C₁₅H₁₀BrN₃O₂S requires: 375, found: 376 [M+H]⁺.

Step 2

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile:A sealed tube was charged with4-bromo-1-tosyl-H-pyrrolo[2,3-b]pyridine-2-carbonitrile (25 mg, 0.066mmol), KOAc (19.6 mg, 0.199 mmol), bis(pinacolato)diboron (20.3 mg,0.0800 mmol), PdCl₂(dppf)-CH₂Cl₂ (2.7 mg, 3.3 μmol) and dioxane (443μL). The reaction mixture was degassed with N₂ for 30 seconds, sealedand heated at 90° C. for 18 h. The reaction mixture was cooled to RT,filtered through CELITE®, washed with EtOAc and concentrated underreduced pressure. The residue was purified via silica gel chromatography(0-80% EtOAc in hexanes) to afford the title compound (11 mg, 20% yield)as a pale yellow liquid.

MS (ES⁺) C₂₁H₂₂BN₃O₄S requires: 423, found: 342 [M-81]⁺.

Intermediate BB

Methyl(R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinateStep 1

Methyl6-(tert-butylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-picolinate:A suspension of methyl 4-bromo-6-(tert-butylamino)picolinate (222 mg,0.773 mmol), Pin₂B₂ (216 mg, 0.850 mmol) and KOAc (228 mg, 2.32 mmol) indioxane (3.87 mL) was degassed with N₂ for 1 minute. PdCl₂(dppf)-CH₂Cl₂(31.6 mg, 0.039 mmol) was added and the mixture was degassed with N₂ foran additional 1 minute. The reaction mixture was heated to 100° C. andstirred for 12 h. The mixture was cooled to RT, filtered through CELITE®and concentrated under reduced pressure. The residue was purified viasilica gel chromatography (0-20% MeOH in CH₂Cl₂) to afford the titlecompound (226 mg, 87% yield) as a brown liquid.

MS (ES⁺) C₁₇H₂₇BN₂O₄ requires: 334, found: 253 [M-81]⁺.

Step 2

Methyl(R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinate:A suspension of Int. D (81 mg, 0.264 mmol), the product from theprevious step (200 mg, 0.599 mmol) and K₂CO₃ (73 mg, 0.53 mmol) in THF(1.2 mL) and water (120 μL) was degassed with N₂ for 1 minute.PdCl₂(dppf)-CH₂Cl₂ (11 mg, 0.013 mmol) was added and the mixture wasdegassed with N₂ for an additional 1 minute. The reaction mixture washeated to 60° C. and stirred for 2 h. The mixture was cooled to RT andthe layers were separated. The aqueous layer was extracted with EtOAc(3×1 mL). The combined organic layers were washed with brine (1 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified via silica gel chromatography (0-60% EtOAc inhexanes) to afford the title compound (150 mg, quantitative yield) as apale yellow liquid.

MS (ES⁺) C₂₂H₃₂N₆O₄S requires: 476, found: 477 [M+H]⁺.

Intermediate CC

(R)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanoneand

(S)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl) (methyl)-λ⁶-sulfanone

(R)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)-(methyl)-λ⁶-sulfanoneand(S)-((2-chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone:To solution of Int. E (47 g, 0.19 mol) and(R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine (synthesized asdescribed for Int. B, step 1) (22 g, 0.19 mol) in dioxane (750 mL) wereadded Pd₂(dba)₃ (8.6 g, 9.4 mmol), XantPhos (5.5 g, 9.4 mmol) and Cs₂CO₃(184 g, 0.57 mol) and the resulting mixture was purged with N₂ (3×),heated to 80° C. and stirred under an atmosphere of N₂ for 6 h. Thereaction mixture was cooled to RT, filtered through CELITE® andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (0-100% EtOAc in hexanes) to afford the titlecompounds as a mixture of two diastereomers of unknown absolutestereochemistry at the sulfur atom (26 g, 41% yield) as an off-whitesolid.

A solution of the mixture of diastereomers (35 g, 0.11 mol) in CH₂Cl₂(300 mL) was separated by Chiral SFC (Mobile phase: CO₂/EtOH=75/25; Flowrate: 70 g/min; 4 min; Column temperature: 35° C.; Back pressure: 100bar; Column: Daicel CHIRALPAK® AD, 10 μm, 20 mm×250 mm) to afford thetwo diastereomers of unknown absolute stereochemistry at the sulfur atomIsomer 1a (15.0 g, 86%) as a light yellow solid and Isomer 1b (14.2 g,81%) as a light yellow solid.

Isomer 1a ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (400 MHz, CDCl₃) δ 5.69(s, 1H), 4.15-4.05 (m, 1H), 3.93-3.79 (m, 2H), 3.67 (d, J=11.5 Hz, 1H),3.59 (app. d, J=11.5 Hz, 1H), 3.51-3.39 (m, 1H), 3.36 (s, 3H), 3.12 (td,J=12.8, 3.4 Hz, 1H), 2.87-2.76 (m, 1H), 1.51-1.40 (m, 1H), 1.28-1.21 (m,1H), 1.19 (d, J=6.7 Hz, 3H), 1.14-0.99 (m, 2H); MS (ES⁺) C₁₃H₁₉CN₄O₂Srequires: 330, found: 331 [M+H]⁺; R_(t)=3.19 min.

Isomer 1b ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (400 MHz, CDCl₃) δ 5.68(s, 1H), 4.14-4.05 (m, 1H), 3.88 (dd, J=11.5, 3.9 Hz, 1H), 3.83 (d,J=13.6 Hz, 1H), 3.67 (d, J=11.5 Hz, 1H), 3.59 (dd, J=11.5, 3.2 Hz, 1H),3.45 (td, J=11.9, 3.1 Hz, 1H), 3.37 (s, 3H), 3.12 (td, J=12.8, 3.9 Hz,1H), 2.81 (ddd, J=12.8, 8.0, 4.8 Hz, 1H), 1.49-1.41 (m, 1H), 1.27-1.20(m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.14-1.01 (m, 2H); MS (ES⁺)C₁₃H₁₉ClN₄O₂S requires: 330, found: 331 [M+H]⁺; R_(t)=5.62 min.

Intermediate DD

Imino(methyl)(pyridin-3-yl)-λ⁶-sulfanone

Imino(methyl)(pyridin-3-yl)-λ⁶-sulfanone: To a solution of3-(methylthio)pyridine (1.09 g, 8.72 mmol) in MeOH (10 mL) were addedNH₂COONH₄ (1.7 g, 21.8 mmol) and PhI(OAc)₂ (7.02 g, 21.8 mmol) and theresulting mixture was stirred for 3 h. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by reversephase preparative HPLC (Mobile Phase: A=10 mM NH₄HCO₃ in H₂O, B=MeCN;Gradient: B=95%; 13 min; 30 mL/min; column: Xtimate Prep C18 OBD21.2×250 mm, 10 μm) to afford the title compound (760 mg, 55%) as anoff-white solid.

(ES⁺) C₆H₈N₂OS requires: 156, found: 157 [M+H]⁺.

Intermediate EE

Imino(methyl)(1-methyl-1H-pyrazol-4-yl)-λ⁶-sulfanone Step 1

1-Methyl-4-(methylthio)-1H-pyrazole: To a solution of4-iodo-1-methyl-1H-pyrazole (0.5 mL, 5.2 mmol) in THF (2 mL) at −78° C.under an atmosphere of N₂ was added isopropylmagnesium chloride (5.2 mL,10.4 mmol) and the resulting mixture was stirred for 30 minutes. To thereaction mixture was added dimethyl disulfide (1 mL, 11 mmol). Thereaction was poured into aq. sat. NH₄Cl (25 mL), the layers wereseparated and the aqueous layer was extracted with Et₂O (100 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by reversephase preparative HPLC (Mobile Phase: A=10 mM NH₄HCO₃ in H₂O, B=MeCN;Gradient: B=95%; 13 min; 30 mL/min; column: Xtimate Prep C18 OBD21.2×250 mm, 10 μm) to afford the title compound (740 mg, 29%) as anoff-white solid.

(ES⁺) C₅H₈N₂S requires: 128, found: 129 [M+H]⁺.

Step 2

Imino(methyl)(1-methyl-1H-pyrazol-4-yl)-λ⁶-sulfanone: To solution of theproduct from the previous step (1.09 g, 8.72 mmol) in MeOH (10 mL) wereadded NH₂COONH₄ (1.7 g, 21.8 mmol) and PhI(OAc)₂ (7.02 g, 21.8 mmol) andthe resulting mixture was stirred for 3 h. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by reversephase preparative HPLC (Mobile Phase: A=10 mM NH₄HCO₃ in H₂O, B=MeCN;Gradient: B=95%; 13 min; 30 mL/min; column: Xtimate Prep C18 OBD21.2×250 mm, 10 μm) to afford the title compound (730 mg, 53%) as anoff-white solid.

(ES⁺) C₅H₉N₃OS requires: 159, found: 160 [M+H]⁺.

Intermediate FF

2-(((Triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazole

2-(((Triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazole: To a solutionof (1H-benzo[d]imidazol-2-yl)methanol (1.66 g, 11.2 mmol), imidazole(0.92 g, 13 mmol) and DMAP (0.068 g, 0.56 mmol) in DMF (10 mL) was addedneat TIPSCl (2.87 mL, 13.4 mmol) and the resulting mixture was stirredat RT for 48 h. The reaction mixture was poured into water (100 mL), thelayers were separated and the aqueous layer was extracted with Et₂O(2×100 mL). The combined organic layers were washed with water (2×100mL) followed by brine (100 mL), stirred over MgSO₄, filtered andconcentrated under reduced pressure to afford the title compound (3.40g, 99% yield) as a white solid.

MS (ES⁺) C₁₇H₂₈N₂OSi requires: 304 found: 305 [M+H]⁺.

EXAMPLE 1

(R)-dimethyl((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-4-yl)imino)-λ⁶-sulfanone

(R)-dimethyl((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanoneA reaction vial was charged with Int. B (100 mg, 0.30 mmol), Int. C (34mg, 0.36 mmol), RuPhos Pd G4 (26 mg, 0.030 mmol), RuPhos (14 mg, 0.030mmol), Cs₂CO₃ (293 mg, 0.90 mmol) and 1,4-dioxane (2 mL). The vial waspurged with N₂ and sealed. The reaction mixture was stirred at 85° C.for 16 h. The reaction mixture was cooled to RT, filtered throughCELITE®, and concentrated under reduced pressure. The residue waspurified by reverse phase preparative HPLC (Mobile phase: A=10 MNH₄HCO₃/H₂O, B=MeCN; Gradient: B=20-50%; 10 min; Column: Venusil ASBC18, 10 μm, 150A, 21.2 mm×250 mm) to afford the title compound (33.0 mg,28% yield) as a white solid.

¹H NMR (500 MHz, DMSO) δ 11.72 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 7.89 (d,J=5.0 Hz, 1H), 7.59-7.49 (m, 1H), 7.41 (dd, J=3.3, 1.9 Hz, 1H), 5.92 (s,1H), 4.45 (s, 1H), 4.06 (d, J=12.8 Hz, 1H), 3.96 (dd, J=11.3, 3.4 Hz,1H), 3.75 (d, J=11.3 Hz, 1H), 3.64 (dd, J=11.3, 2.9 Hz, 1H), 3.53-3.47(m, 1H), 3.45 (s, 6H), 3.15 (td, J=12.8, 3.8 Hz, 1H), 1.20 (d, J=6.7 Hz,3H); MS (ES⁺) C₁₈H₂₂N₆O₂S requires: 386, found: 387 [M+H]⁺.

The compounds reported in Table 2were synthesized using the methoddescribed for the previously disclosed Examples. The appropriatesulfoximines were prepared as described for Intermediates C.

TABLE 1 Example compounds 2-9 Ex. Ex Structure IUPAC Name MWt [M + H]Method 2

1-({6-[(3R)-3-methyl- morpholin-4-yl]-2-{1H- pyrrolo[2,3-b]pyridin-4-yl}pyrimidin-4-yl}- imino)-1λ⁶-thiolan-1-one 412 413 1 3

diethyl ({6[(3R)-3- methylmorpholin-4-yl]- 2-{1H-pyrrolo[2,3-b]-pyridin-4-yl}pyrimidin- 4-yl}imino)-λ⁶-sulfanone 414 415 1 4

1-({6-[(3R)-3-methyl- morpholin-4-yl]-2-{1H- pyrrolo[2,3-b]pyridin-4-yl}pyrimidin-4-yl}- imino)-1λ⁶-thian-1-one 426 427 1 5

4-({6-[(3R)-3-methyl- morpholin-4-yl]-2-{1H- pyrrolo[2,3-b]pyridin-4-yl}pyrimidin-4-yl}- imino)-4λ⁶-1,4-oxathian- 4-one 428 429 1 6

methyl tetrahydropyran- 4-yl ({6-[(3R)-3-methyl- morpholin-4-yl]-2-{1H-pyrrolo[2,3-b]pyridin-4- yl}pyrimidin-4-yl}- imino)-λ⁶-sulfanone 456 4571 7

methyl ethyl ({6-[(3R)-3- methylmorpholin-4-yl]- 2-{1H-pyrrolo[2,3-b]-pyridin-4-yl}pyrimidin- 4-yl}imino)-λ⁶-sulfanone 400 401 1 8

methyl 2-propyl ({6- [(3R)-3-methyl- morpholin-4-yl]-2-{1H-pyrrolo[2,3-b]pyridin-4- yl}pyrimidin-4-yl}- imino)-λ₆-sulfanone 414 4151 9

methyl (cyclopropyl)- methyl ({6-[(3R)-3- methylmorpholin-4-yl]-2-{1H-pyrrolo[2,3-b]- pyridin-4-yl}pyrimidin- 4-yl}imino)-λ⁶-sulfanone426 427 1

EXAMPLE 10

(R)-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanoneStep 1

(R)-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A solution of Int. D (45 mg, 0.148 mmol), Int. P (101 mg, 0.192 mmol)and K₂CO₃ (51 mg, 0.37 mmol) in dioxane (671 μL) and water (67 μL) wasdegassed with a stream of N₂ for 1 minute. PdCl₂(dppf)-CH₂Cl₂ (6.0 mg,7.9 μmol) was added, the mixture was degassed with a stream of N₂ for anadditional 1 minute., and the reaction mixture was heated at 85° C. for3 h. The reaction mixture was cooled to RT, filtered through CELITE®,washed with CH₂Cl₂ (2 mL) and concentrated under reduced pressure. Theresidue was purified by mass-triggered preparative HPLC (Mobile phase:A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min; Column:XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (32 mg,34% yield) as a pale yellow solid.

¹H NMR (600 MHz, Methanol-d4) δ 8.31 (d, J=3.0 Hz, 1H), 7.66 (d, J=3.4Hz, 1H), 6.71 (d, J=3.5 Hz, 1H), 6.31 (s, 1H), 4.63 (s, 1H), 4.19 (s,1H), 4.04 (dd, J=11.9, 3.8 Hz, 1H), 3.83 (d, J=11.8 Hz, 1H), 3.75 (dd,J=11.9, 3.2 Hz, 1H), 3.61 (td, J=11.9, 2.9 Hz, 1H), 3.57 (d, J=5.4 Hz,6H), 3.51 (t, J=13.5 Hz, 1H), 1.42 (d, J=6.8 Hz, 3H); MS (ES⁺)C₁₈H₂₁FN₆O₂S requires: 404, found: 405 [M+H]⁺.

EXAMPLE 11

(R)-Dimethyl((2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanoneStep 1

(R)-dimethyl((2-(2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone:A reaction vial was charged with Int. D (103 mg, 0.5 mmol), Int. G (280mg, 0.68 mmol), Na₂CO₃ (216 mg, 2.04 mmol), PdCl₂(dppf) (25 mg, 0.034mmol), dioxane (3 mL) and H₂O (1 mL). The vial was purged with N₂ andsealed. The reaction mixture was stirred at 80° C. for 3 h. The reactionmixture was cooled to RT, filtered through CELITE® and concentratedunder reduced pressure. The residue was purified by prep-TLC (50% EtOAcin hexanes) to afford the title compound (50 mg, 26% yield) as a whitesolid.

MS (ES⁺) C₂₆H₃₀N₆O₄S2 requires: 554, found: 555 [M+H]⁺.

Step 2

(R)-Dimethyl((2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone:A mixture of the product from the previous step (50 mg, 0.09 mmol), NaOH(72 mg, 1.8 mmol), H₂O (1 mL) and MeOH (2 mL) was stirred at 70° C. for2 h. The reaction mixture was cooled to RT and concentrated underreduced pressure. MeOH (30 mL) was added, the mixture was stirred for 5min, filtered and concentrated under reduced pressure. The residue waspurified by reverse phase preparative HPLC (Mobile phase: A=10 mMNH₄HCO₃/H₂O, B=MeCN; Gradient: B=30-60%; 18 min; Column: Welch XB-C18,10 μm, 150 Å, 21.2 mm×250 mm) to afford the title compound (15 mg, 41%yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 11.53 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.81(d, J=4.8 Hz 1H), 7.11 (s, 1H), 5.89 (s, 1H), 4.44 (s, 1H), 4.04 (s,1H), 3.95 (s, 1H), 3.75 (d, J=12.6 Hz, 1H), 3.65 (s, 1H), 3.47 (d,J=19.4 Hz, 7H), 3.14 (s, 1H), 2.42 (s, 3H), 1.20 (d, J=6.7 Hz, 3H); MS(ES⁺) C₁₉H₂₄N₆O₂S requires: 400, found: 401 [M+H]⁺.

EXAMPLE 12

(R)-1-(1-((6-(3-Methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1-oxido-1λ⁶-thiomorpholino)ethan-1-oneStep 1

Tert-butyl(R)-1-((6-(3-methylmorpholino)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1λ⁶-thiomorpholine-4-carboxylate1-oxide A mixture Int. R (145 mg, 0.62 mmol), Int. T (300 mg, 0.62mmol), Pd₂(dba)₃ (57 mg, 0.062 mmol), X-phos (30 mg, 0.062 mmol) andCs₂CO₃ (407 mg, 1.24 mmol) in dioxane (10 mL) was degassed with Ar for 5minutes. The reaction mixture was heated to 100° C. and stirred for 3 h.The mixture was cooled to RT, filtered through CELITE® and concentratedunder reduced pressure. The residue was purified via silica gelchromatography (0-50% EtOAc in hexanes) to afford the title compound(310 mg, 73% yield) as a yellow solid.

MS (ES⁺) C₃₂H₃₉N₇O₆S2 requires: 681, found: 682 [M+H]⁺.

Step 2

(R)-1-((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1λ⁶-thiomorpholine1-oxide A mixture of the product from the previous step (300 mg, 0.44mmol), TFA (1 mL) and CH₂Cl₂ (5 mL) was stirred at RT for 1 h. Thereaction mixture was concentrated under reduced pressure to give ayellow oil. MeOH (5 mL) and NaOH (18 mg, 0.88 mmol) were added and themixture was stirred at 60° C. for 1 h. The mixture was cooled to RT, H₂O(10 mL) was added and the aqueous layer was extracted with CH₂Cl₂ (3×15mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound (150mg, 80% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 11.78 (s, 1H), 9.03 (s, 1H), 8.31 (d, J=5.1Hz, 1H), 7.86 (d, J=5.0 Hz, 1H), 7.57 (s, 1H), 7.33 (s, 1H), 6.07 (s,1H), 4.50 (s, 1H), 3.98 (d, J=11.4 Hz, 6H), 3.87-3.82 (m, 3H), 3.52 (s,4H), 3.19 (s, 1H), 1.23 (d, J=6.7 Hz, 3H); MS (ES⁺) C₂₀H₂₅N₇O₂Srequires: 427, found: 428 [M+H]⁺.

Step 3

(R)-1-(1-((6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-1-oxido-1λ⁶-thiomorpholino)ethan-1-one:To a solution of the product from the previous step (100 mg, 0.23 mmol)and Et₃N (0.5 mL, 0.5 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added acetylchloride (18 mg, 0.23 mmol) and the resulting mixture was warmed to RTand stirred for 30 minutes. The reaction mixture was filtered andconcentrated under reduced pressure. The residue was purified by reversephase preparative HPLC (Mobile phase: A=10 mM NH₄HCO₃/H₂O, B=MeCN;Gradient: B=25-55%; 15 min; Column: Welch XB-C18, 10 μm, 21.2×250 mm) toafford the title compound (36 mg, 33% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 11.72 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.86(d, J=5.0 Hz, 1H), 7.59-7.50 (m, 1H), 7.37 (dd, J=3.2, 2.0 Hz, 1H), 6.02(s, 1H), 4.49 (s, 1H), 4.18 (s, 1H), 4.11-3.82 (m, 4H), 3.79-3.56 (m,6H), 3.53-3.39 (m, 2H), 3.17 (s, 1H), 2.07 (d, J=2.0 Hz, 3H), 1.22 (d,J=6.6 Hz, 3H); MS (ES⁺) C₂₂H₂₇N₇O₃S requires: 469, found: 470 [M+H]⁺.

EXAMPLE 13

(R)-((2-(2-amino-6-chloropyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanoneStep 1

(R)-((2-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A solution of Int. D (150 mg, 0.492 mmol), Int. Y (516 mg, 0.689 mmol)and K₂CO₃ (170 mg, 1.23 mmol) in dioxane (2.2 mL) and water (224 μL) wasdegassed with N₂ for 1 minute. PdCl₂(dppf)-CH₂Cl₂A (20.1 mg, 0.025 mmol)was added and the mixture was degassed with N₂ for an additional 1minute. The reaction mixture was heated at 85° C. for 3 h. The reactionmixture was cooled to RT, filtered through CELITE®, washed with CH₂Cl₂and concentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=40-80%; 16 min; Column: XBridge C18, 5 μm, 19mm×150 mm) to afford the title compound (166 mg, 23% yield) as a paleyellow solid.

MS (ES⁺) C₂₄H₂₉ClN₆O₃S requires: 516, found: 517 [M+H]⁺.

Step 2

(R)-((2-(2-amino-6-chloropyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:To a solution of the product from the previous step (32 mg, 0.021 mmol)in CH₂Cl₂ (215 μL) was added TFA (33 μL, 0.43 mmol) and the resultingmixture was stirred at RT for 2 h. The reaction mixture was concentratedunder reduced pressure. The residue was purified by mass-triggeredpreparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN;Gradient: B=20-60%; 20 min; Column: XBridge C18, 5 μm, 19 mm×150 mm) toafford the title compound (12.2 mg, 91% yield) as an off-white solid.

¹H NMR (600 MHz, Methanol-d₄) δ 7.15 (d, J=1.0 Hz, 1H), 7.10 (s, 1H),6.20 (s, 1H), 4.58 (s, 1H), 4.19 (s, 1H), 4.03 (dd, J=11.6, 3.9 Hz, 1H),3.83 (d, J=11.7 Hz, 1H), 3.73 (dd, J=11.7, 3.2 Hz, 1H), 3.59 (td,J=12.0, 3.1 Hz, 1H), 3.53 (d, J=4.1 Hz, 6H), 3.42 (td, J=13.1, 3.8 Hz,1H), 1.37 (d, J=6.8 Hz, 3H); MS (ES⁺) C₁₆H₂₁ClN₆O₂S requires: 396/398,found 397/399 [M+H]⁺.

EXAMPLE 14

(R)-((2-(2-amino-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanoneStep 1

(R)-((2-(2-((4-methoxybenzyl)amino)-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A solution of(R)-((2-(2-chloro-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone(synthesized as described for Example 13, step 1) (50 mg, 0.034 mmol),methylboronic acid (2.410 mg, 0.040 mmol) and K₂CO₃ (11.6 mg, 0.084mmol) in dioxane (153 μL) and water (15 μL) was degassed with N₂ for 30seconds PdCl₂(dppf)-CH₂Cl2 (1.4 mg, 1.7 μmol) was added and the mixturewas degassed with N₂ for an additional 30 seconds. and the resultingmixture was heated at 120° C. for 6 h in a microwave reactor. Thereaction mixture was cooled to RT, filtered through CELITE®, washed withCH₂Cl₂ and concentrated under reduced pressure. The residue was purifiedby mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=10-40%; 26 min; Column: XBridge C18, 5 μm, 19mm×150 mm) to afford the title compound (13.5 mg, 56% yield) as a paleyellow solid.

MS (ES⁺) C₂₅H₃₂N₆O₃S requires: 496, found: 497 [M+H]⁺.

Step 2

(R)-((2-(2-amino-6-methylpyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:To a solution of the product from the previous step (13.5 mg, 0.019mmol) in CH₂Cl₂ (186 μL) was added TFA (29 μL, 0.37 mmol) and theresulting mixture was stirred at RT for 2 h. The reaction mixture wasconcentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=10-40%; 20 min; Column: XBridge C18, 5 μm, 19mm×150 mm) to afford the title compound (8.6 mg, 76% yield) as anoff-white solid.

¹H NMR (600 MHz, Methanol-d4) δ 7.69 (s, 1H), 7.47 (s, 1H), 6.04 (s,1H), 4.51-4.45 (m, 1H), 4.09 (d, J=12.9 Hz, 1H), 4.00 (dd, J=11.5, 3.9Hz, 1H), 3.80 (d, J=11.5 Hz, 1H), 3.72 (dd, J=11.6, 3.2 Hz, 1H), 3.57(td, J=11.9, 3.2 Hz, 1H), 3.49 (s, 6H), 3.32-3.24 (m, overlap MeOH, 1H),2.55 (s, 3H), 1.29 (d, J=6.8 Hz, 3H); MS (ES⁺) C₁₇H₂₄N₆O₂S requires:376, found 377 [M+H]⁺.

EXAMPLE 15

(R)-6-amino-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinonitrile

(R)-6-amino-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinonitrile:A microwave vial was charged with Example 13 (95 mg, 0.076 mmol),Pd₂(dba)₃ (7.0 mg, 7.6 μmol), DPPF (2.1 mg, 3.8 μmol), zinc (0.75 mg,0.011 mmol), dicyanozinc (8.9 mg, 0.076 mmol) and DMA (380 μL). The vialwas sealed and the reaction mixture was heated to 150° C. in a microwavereactor for 3 h. The reaction mixture was cooled to RT and directlypurified by mass-triggered preparative HPLC (Mobile phase: A=0.1%TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-50%; 26 min; Column: XBridgeC18, 5 μm, 19 mm×150 mm) to afford the title compound (23.3 mg, 50%yield) as a pale yellow solid.

¹H NMR (600 MHz, Methanol-d4) δ 7.58 (s, 1H), 7.44 (s, 1H), 6.19 (s,1H), 4.58 (s, 1H), 4.28-4.10 (m, 1H), 4.03 (dd, J=11.7, 3.9 Hz, 1H),3.83 (d, J=11.7 Hz, 1H), 3.73 (dd, J=11.7, 3.2 Hz, 1H), 3.59 (td,J=12.0, 3.1 Hz, 1H), 3.54 (d, J=4.4 Hz, 6H), 3.41 (td, J=13.0, 4.0 Hz,1H), 1.37 (d, J=6.9 Hz, 3H); MS (ES⁺) C₁₇H₂₁N₇O₂S requires: 387, found:388 [M+H]⁺.

EXAMPLE 16

Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanoneStep 1

Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone:A reaction vial was charged with Int. T (300 mg, 0.60 mmol), Int. E (80mg, 0.67 mmol), Cs₂CO₃ (655 mg, 2.01 mmol), RuPhos Pd G3 (56 mg, 0.067mmol), RuPhos (31 mg, 0.067 mmol) and dioxane (4 mL). The reactionmixture was purged with N₂, sealed and heated at 80° C. for 3 h. Thereaction mixture was cooled to RT, filtered through CELITE® andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (0-50% acetone in hexanes) to afford the titlecompound (130 mg, 37% yield) as a white solid.

MS (ES⁺) C₂₇H₃₀N₆O₄S₂ requires: 566, found: 567 [M+H]⁺.

Step 2

Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone:A reaction vial was charged with the product from the previous step (130mg, 0.23 mmol), NaOH (184 mg, 4.6 mmol), H₂O (1 mL) and MeOH (2 mL) andthe mixture was heated at 70° C. for 2 h. The reaction mixture wascooled to RT and concentrated under reduced pressure. The residue wasadded MeOH (30 mL) and the resulting mixture was stirred for 5 min.,filtered and concentrated under reduced pressure. The residue waspurified by reverse phase preparative HPLC (Mobile phase: A=10 mMNH₄HCO₃/H₂O, B=MeCN; Gradient: B=30-60%; 18 min; Column: Welch XB-C18,10 μm, 150 Å, 21.2 mm×250 mm) to afford the title compound (20 mg, 21%yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 11.71 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.90(dd, J=5.0, 1.8 Hz, 1H), 7.53 (d, J=2.9 Hz, 1H), 7.40 (s, 1H), 5.95 (s,1H), 4.47 (s, 1H), 4.05 (s, 1H), 3.96 (d, J=8.5 Hz, 1H), 3.75 (d, J=11.2Hz, 1H), 3.64 (d, J=11.4 Hz, 1H), 3.52 (t, J=13.9 Hz, 4H), 3.16 (s, 1H),3.00 (s, 1H), 1.18 (dd, J=34.3, 27.3 Hz, 7H); MS (ES⁺) C₂H₂₄N₆O₂Srequires: 412, found: 413 [M+H]⁺.

EXAMPLE 17a and 17b

(S)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanoneand

(R)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanoneStep 1

(S)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanoneand(R)-ethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone:To a solution ofethyl(methyl)((6-((R)-3-methylmorpholino)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone(synthesis is similar to that described for Example 16) (350 mg, 0.63mmol) in MeOH (6 mL) and THF (2 mL) was added NaOH (1.5 mL, 4 N aqueous)and the reaction mixture was heated to 60° C. and stirred for 2 h. Thereaction mixture was cooled to RT and concentrated under reducedpressure. The residue was purified via silica gel chromatography (0-5%MeOH in CH₂Cl₂) to afford a mixture of the title compounds. The mixtureof diastereomers was separated by Chiral SFC (Mobile phase: CO₂/ethanol(1% MeOH Ammonia)=45/55; Flow rate: 80 g/min; 6.5 min; Columntemperature: 35° C.; Back pressure: 100 bar; Column: Daicel CHIRALPAK®AD, 10 μm, 20 mm×250 mm) to afford the two diastereomers of unknownabsolute stereochemistry at the sulfur atom, title compounds 17a (43 mg,18% yield, >99% ee) as a white solid and 17b (47 mg, 20% yield, >94% ee)as a white solid.

17a ((R)-ethyl(methyl)-λ⁶-sulfanone or (S)-ethyl (methyl)-λ⁶-sulfanone):¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.88(d, J=5.0 Hz, 1H), 7.63-7.48 (m, 1H), 7.42 (d, J=2.0 Hz, 1H), 5.93 (s,1H), 4.44 (s, 1H), 4.07 (d, J=12.7 Hz, 1H), 3.96 (dd, J=11.3, 3.2 Hz,1H), 3.75 (d, J=11.3 Hz, 1H), 3.63 (dd, J=9.1, 5.7 Hz, 2H), 3.61 (d,J=7.5 Hz, 1H), 3.49 (td, J=11.8, 2.8 Hz, 1H), 3.38 (s, 3H), 3.15 (td,J=12.8, 3.6 Hz, 1H), 1.31 (t, J=7.4 Hz, 3H), 1.21 (t, J=7.3 Hz, 3H); MS(ES⁺) C₁₉H₂₄N₆O₂S requires: 400, found: 401 [M+H]⁺; R_(t)=2.72 min.

17b ((R)-ethyl(methyl)-λ⁶-sulfanone or (S)-ethyl (methyl)-λ⁶-sulfanone):¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.88(d, J=5.0 Hz, 1H), 7.54 (d, J=3.4 Hz, 1H), 7.42 (d, J=3.3 Hz, 1H), 5.93(s, 1H), 4.47 (s, 1H), 4.05 (d, J=13.2 Hz, 1H), 3.96 (dd, J=11.1, 3.4Hz, 1H), 3.75 (d, J=11.4 Hz, 1H), 3.70-3.53 (m, 3H), 3.54-3.44 (m, 1H),3.36 (d, J=13.0 Hz, 3H), 3.15 (td, J=12.7, 3.6 Hz, 1H), 1.32 (q, J=7.7Hz, 3H), 1.21 (d, J=6.7 Hz, 3H); MS (ES⁺) C₁₉H₂₄N₆O₂S requires: 400,found: 401 [M+H]⁺; R_(t)=3.28 min.

EXAMPLE 18 (18a and 18b)

(R)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanoneand

(S)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanoneStep 1

Cyclopropyl((2-(2-methoxy-6-((4-methoxybenzyl)amino)pyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)-λ⁶-sulfanone:A suspension of Int. Q (590 mg, 1.79 mmol), Int. S (790 mg, 2.14 mmol)and K₂CO₃ (741 mg, 5.37 mmol) in dioxane (15 mL) and water (3 mL) wasdegassed with N₂ for 1 minute. PdCl₂(dppf)-CH₂Cl2 (73 mg, 0.090 mmol)was added and the mixture was degassed with N₂ for an additional 1minute. The reaction mixture was heated to 130° C. in a microwavereactor for 4 h. The mixture was cooled to RT, the layers were separatedand the organic layer was concentrated under reduced pressure. Theresidue was purified via silica gel chromatography (0-2% MeOH in CH₂Cl₂)to afford the title compound (910 mg, 95% yield) as a yellow solid.

MS (ES⁺) C₂₇H₃₄N₆O₄S requires: 538, found: 539 [M+H]⁺.

Step 2

(S)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanoneand(R)-((2-(2-Amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone:To a solution of the product from the previous step (910 mg, 1.69 mmol)in CH₂Cl₂ (7 mL) was added TFA (2.5 mL, 34 mmol) and the resultingmixture was stirred at 45° C. for 16 h. The mixture was cooled to RT andneutralized with 6 N NaOH to pH=7, followed by the addition of sat. aq.NaHCO₃(30 mL) and the mixture was stirred vigorously for 5 min. Theaqueous layer was extracted with CH₂Cl₂ (3×50 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified via silica gel chromatography (0-3%MeOH in CH₂Cl₂) to afford a mixture of the title compounds (650 mg, 92%yield). The mixture of diastereomers was separated by Chiral SFC (Mobilephase: CO₂/MeOH (0.2% MeOH Ammonia)=45/55; Flow rate: 80 g/min; 7 min;Column temperature: 35° C.; Back pressure: 100 bar; Column: DaicelCHIRALPAK® AD, 10 μm, 20 mm×250 mm) to afford the two diastereomers ofunknown absolute stereochemistry at the sulfur atom, compounds 18a (167mg, 26% yield, 98.6% ee) as a white solid and 18b (230 mg, 35%yield, >99% ee) as a white solid; (R)-cyclopropyl(methyl)-λ⁶-sulfanoneand (S)-cyclopropyl(methyl)-λ⁶-sulfanone

18a: ¹H NMR (400 MHz, DMSO-d₆) δ 6.87 (s, 1H), 6.67 (s, 1H), 6.00 (s,2H), 5.90 (s, 1H), 4.44-4.34 (m, 1H), 4.02 (d, J=13.2 Hz, 1H), 3.92 (dd,J=11.3, 3.2 Hz, 1H), 3.77 (s, 3H), 3.72 (d, J=11.4 Hz, 1H), 3.60 (dd,J=11.3, 3.1 Hz, 1H), 3.55 (s, 3H), 3.45 (td, J=11.6, 2.6 Hz, 1H), 3.09(td, J=12.7, 3.8 Hz, 1H), 3.06-2.94 (m, 1H), 1.25-1.19 (m, 1H), 1.16(app. d, overlap, J=6.6 Hz, 3H), 1.14-1.02 (m, 3H); MS (ES⁺)C₁₋₉H₂₆N₆O₃S requires: 418, found: 419 [M+H]⁺; R_(t)=3.03 min.

18b: ¹H NMR (500 MHz, DMSO-d₆) δ 6.88 (d, J=1.2 Hz, 1H), 6.68 (d, J=1.1Hz, 1H), 5.99 (s, 2H), 5.90 (s, 1H), 4.43-4.34 (m, 1H), 4.03 (d, J=13.3Hz, 1H), 3.92 (dd, J=11.3, 3.6 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J=11.3Hz, 1H), 3.60 (dd, J=11.4, 3.1 Hz, 1H), 3.55 (s, 3H), 3.45 (td, J=11.8,3.1 Hz, 1H), 3.09 (td, J=12.8, 3.8 Hz, 1H), 3.01 (tt, J=7.9, 4.9 Hz,1H), 1.25-1.19 (m, 1H), 1.16 (app. d, overlap, J=6.7 Hz, 3H), 1.14-1.05(m, 2H); MS (ES⁺) C₁₉H₂₆N₆O₃S requires: 418, found: 419 [M+H]⁺; Rt=3.71min.

Alternatively, Example 18b can also be prepared from Int. CC, Isomer 1b.

EXAMPLE 19

(R)-((2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanoneStep 1

(R)-((2-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A suspension of Int. K (278 mg, 1.00 mmol), Int. D (304 mg, 1.00 mmol),Na₂CO₃ (212 mg, 2.00 mmol) and PdCl₂(dppf) (75 mg, 0.1 mmol) in dioxane(20 mL) and H₂O (4 mL) was degassed with Ar (3×). The reaction mixturewas heated to 80° C. and stirred for 16 h under an atmosphere of Ar. Themixture was cooled to RT, filtered through CELITE® and concentratedunder reduced pressure. The residue was purified by Prep-TLC (66% EtOAcin petroleum ether) to afford the title compound (130 mg, 31% yield) asa white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 11.98 (s, 1H), 7.86 (s, 1H), 7.59 (s, 1H),7.45 (s, 1H), 5.95 (s, 1H), 4.42 (s, 1H), 4.01 (dd, J=43.8, 11.0 Hz,2H), 3.75 (d, J=11.2 Hz, 1H), 3.63 (d, J=9.8 Hz, 1H), 3.46 (d, J=22.0Hz, 7H), 3.16 (d, J=12.4 Hz, 1H), 1.20 (d, J=6.6 Hz, 3H); MS (ES⁺)C₁₈H₂₁CN₆O₂S requires: 420, found: 421 [M+H]⁺.

EXAMPLE 20

(R)-4-(4-((dimethyl(oxo)-λ⁶-sulfanylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrileStep 1

(R)-4-(4-((dimethyl(oxo)-λ⁶-sulfanylidene)amino)-6-(3-methylmorpholino)-pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile:A mixture of Example 19 (40 mg, 0.096 mmol), ZnCN₂ (113 mg, 0.96 mmol)and Pd(PPh₃)₄ (110 mg, 0.096 mmol) in DMF (3 mL) was degassed with Ar.The reaction mixture was heated at 150° C. for 2 h in a microwavereactor. The mixture was cooled to RT, filtered through CELITE® andconcentrated under reduced pressure. The residue was purified by reversephase preparative HPLC (Mobile Phase: A=10 mM NH₄HCO₃ in H₂O, B=MeCN;Gradient: B=35-65%; 18 min; 30 mL/min; column: Welch XB-C18 21.2×250 mm,10 μm) to afford the title compound (13 mg, 33% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 12.38 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H),7.61 (d, J=3.0 Hz, 1H), 5.96 (s, 1H), 4.44 (s, 1H), 4.09 (d, J=12.5 Hz,1H), 3.97 (d, J=8.5 Hz, 1H), 3.75 (d, J=11.5 Hz, 1H), 3.64 (d, J=8.7 Hz,1H), 3.53-3.41 (m, 7H), 3.16 (t, J=10.9 Hz, 1H), 1.20 (d, J=6.7 Hz, 3H);MS (ES⁺) C₁₉H₂₁N₇O₂S requires: 411, found: 412 [M+H]⁺.

EXAMPLE 21

(R)-dimethyl((2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanoneStep 1

(R)-dimethyl((2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methyl-morpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone:A mixture of Example 19 (30 mg, 0.07 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (9 mg, 0.07 mmol),PdCl₂(dppf) (5 mg, 0.007 mmol) and Cs₂CO₃ (70 mg, 0.21 mmol) in dioxane(6 mL) and H₂O (1 mL) was degassed with Ar and heated to 80° C. andstirred for 16 h. The reaction mixture was cooled to RT, filteredthrough CELITE® and concentrated under reduced pressure. The residue waspurified by reverse phase preparative HPLC (Mobile Phase: A=10 mMNH₄HCO₃ in water, B=MeCN; Gradient: B=30-60%; 18 min; 30 mL/min; column:Welch XB-C18 21.2×250 mm, 10 μm) to afford the title compound (4 mg, 14%yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 11.50 (s, 1H), 7.75 (s, 1H), 7.41 (d, J=2.7Hz, 1H), 7.33 (s, 1H), 5.91 (s, 1H), 4.44 (s, 1H), 4.07 (d, J=13.4 Hz,1H), 3.96 (d, J=7.7 Hz, 1H), 3.75 (d, J=11.4 Hz, 1H), 3.64 (d, J=8.5 Hz,1H), 3.50 (d, J=9.0 Hz, 1H), 3.44 (s, 6H), 2.59 (s, 3H), 1.20 (d, J=6.7Hz, 3H); MS (ES⁺) C₁₉H₂₄N₆O₂S requires: 400, found: 401 [M+H]⁺.

EXAMPLE 22

(R)-dimethyl((6-(3-methylmorpholino)-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanoneStep 1

(R)-dimethyl((6-(3-methylmorpholino)-2-(1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)pyrimidin-4-yl)imino)-16-sulfanone:A suspension of4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine(60 mg, 0.12 mmol), Int. D (37 mg, 0.12 mmol), Na₂CO₃ (25 mg, 0.24 mmol)and PdCl₂(dppf) (9.0 mg, 0.012 mmol) in dioxane (6 mL) and H₂O (1 mL)was degassed with Ar (3×). The reaction mixture was heated to 80° C. andstirred for 16 h under an atmosphere of Ar. The reaction mixture wascooled to RT, filtered through CELITE® and concentrated under reducedpressure. The residue was purified by Prep-TLC (66% EtOAc in petroleumether) to afford the title compound (45 mg, 60% yield) as a yellow oil.

MS (ES⁺) C₃₆H₃₅N₇O₂S requires: 629, found: 630 [M+H]⁺.

Step 2

(R)-dimethyl((6-(3-methylmorpholino)-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-pyrimidin-4-yl)imino)-λ⁶-sulfanone:A solution of the product from the previous step in TFA (1 mL) andCH₂Cl₂ (4 mL) was stirred at RT for 4 h. The solvent was removed underreduced pressure and the residue was purified by reverse phasepreparative HPLC (Mobile Phase: A=10 mM NH₄HCO₃ in water, B=MeCN;Gradient: B=25-65%; 18 min; 30 mL/min; column: Welch XB-C18 21.2×250 mm,10 um) to afford the title compound (14 mg, 52% yield) as a pale yellowsolid.

¹H NMR (500 MHz, DMSO-d₆) δ 13.72 (s, 1H), 8.93 (s, 1H), 8.64 (d, J=4.7Hz, 1H), 7.99 (d, J=4.8 Hz, 1H), 5.98 (s, 1H), 4.46 (s, 1H), 4.08 (d,J=12.9 Hz, 1H), 3.97 (d, J=8.0 Hz, 1H), 3.76 (d, J=11.4 Hz, 1H), 3.64(d, J=8.4 Hz, 1H), 3.53-3.43 (m, 7H), 3.22-3.07 (m, 1H), 1.21 (d, J=6.7Hz, 3H); MS (ES⁺) C₁₇H₂₁N₇O₂S requires: 387, found: 388 [M+H]⁺.

EXAMPLE 23

(R)-((2-(1H-indazol-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone

(R)-((2-(1H-indazol-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-dimethyl-λ⁶-sulfanone:A mixture of Int. D (0.21 g, 0.69 mmol),1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(0.27 g, 0.83 mmol), K₃PO₄ (0.44 g, 2.1 mmol) and PdCl₂(dppf)-CH₂Cl₂ (40mg, 0.055 mmol) in dioxane (9 mL) and water (2 mL) was degassed with astream of N₂ for ten minutes and then heated to 85° C. for 4 h. Thereaction mixture was cooled to RT and concentrated under reducedpressure. The residue was partitioned between EtOAc (30 mL) and H₂O (30mL), the layers were separated, and the aqueous layer was extracted withEtOAc (2×30 mL). The combined organic layers were washed with brine (50mL), dried over MgSO₄, filtered and concentrated under reduced pressure.The residue was dissolved in MeOH (8 mL) and THF (2 mL) at roomtemperature and to this solution was added concentrated HCl solution(ca. 12 N, 0.1 mL). The reaction mixture was heated to 60° C. for 20minutes then stirred at RT for 18 h. To the reaction mixture was addedsat. aq. NaHCO₃(3 mL) and the mixture was concentrated under reducedpressure. The residue was partitioned between CH₂Cl₂ (25 mL) and H₂O (25mL), the layers were separated and the aqueous layer was extracted withCH₂Cl₂ (2×25 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated under reduced. The residue was purified viasilica gel chromatography (10-30% CH₃CN in CH₂Cl₂) to afford the titlecompound (0.26 g, quantitative yield) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 9.08 (d, J=0.75 Hz, 1H), 8.20 (dd, J=7.28,1.00 Hz, 1H), 7.61 (d, J=8.28 Hz, 1H), 7.46 (dd, J=8.28, 7.28 Hz, 1H),5.91 (s, 1H), 4.39-4.51 (m, 1H), 3.97-4.19 (m, 2H), 3.74-3.90 (m, 2H),3.56-3.73 (m, 2H), 3.45 (d, J=1.51 Hz, 6H), 3.26-3.39 (m, 1H), 1.36 (d,J=6.78 Hz, 3H); MS (ES⁺) C₁₈H₂₂N₆O₂S requires: 386, found: 387 [M+H]⁺.

EXAMPLE 24

(R)-dimethyl((2-(2-(methylamino)pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone

(R)-dimethyl((2-(2-(methylamino)pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)-λ⁶-sulfanone:A microwave vial was charged with Int. L (100 mg, 0.42 mmol), Int. D (65mg, 0.21 mmol), Na₂CO₃ (133 mg, 1.26 mmol), Pd(dppf)Cl₂ (24 mg, 0.03mmol), dioxane (3 mL) and H₂O (1 mL). The vial was purged with N₂ andsealed. The reaction mixture was heated at 80° C. for 3 h. The reactionmixture was cooled to RT, filtered through CELITE® and concentratedunder reduced pressure. The residue was purified by reverse phasepreparative HPLC (Mobile phase: A=10 mM NH₄HCO₃/H₂O, B=MeCN; Gradient:B=25-55%; 18 min; Column: Welch XB-C18, 10 μm, 150 Å, 21.2 mm×250 mm) toafford the title compound (8 mg, 10% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 8.06 (d, J=5.2 Hz, 1H), 7.29 (s, 1H), 7.24(d, J=5.3 Hz, 1H), 6.67 (s, 1H), 5.87 (s, 1H), 4.42-4.36 (m, 1H),4.07-4.01 (m, 1H), 3.92 (d, J=12.1 Hz, 1H), 3.72 (d, J=11.3 Hz, 1H),3.61 (d, J=8.5 Hz, 1H), 3.45 (d, J=2.5 Hz, 6H), 3.31 (s, 1H), 3.09 (s,1H), 2.80 (d, J=4.8 Hz, 3H), 1.16 (d, J=6.8 Hz, 3H); MS (ES⁺)C₁₇H₂₄N₆O₂S requires: 376, found: 377 [M+H]⁺.

EXAMPLE 25

(R)-((2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone

(R)-((2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A microwave vial was charged with Int. V (34 mg, 0.06 mmol),4-bromo-6-methoxy-1H-pyrrolo[2,3-b]pyridine (14 mg, 0.06 mmol), CuI (1.2mg, 0.006 mmol), LiCl (5 mg, 0.12 mmol), Pd(PPh₃)₄ (7 mg, 0.006 mmol)and DMF (5 mL). The vial was purged with Ar, sealed and heated at 120°C. for 2 h in a microwave reactor. The reaction mixture was cooled toRT, sat. aq. KF (10 mL) was added and the aqueous layer was extractedwith EtOAc (3×10 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by reverse phase preparative HPLC (Mobile phase: A=10 mMNH₄HCO₃/H₂O, B=MeCN; Gradient: B=40-70%; 18 min; Column: Welch XB-C18,10 μm, 21.2×250 mm) to afford the title compound (5 mg, 20% yield) as awhite solid.

¹H NMR (500 MHz, DMSO-d₆) δ 11.55 (s, 1H), 7.35 (s, 1H), 7.26 (d, J=11.3Hz, 2H), 5.92 (s, 1H), 4.43 (s, 1H), 4.03 (d, J=12.7 Hz, 1H), 3.95 (d,J=7.6 Hz, 1H), 3.91 (s, 3H), 3.75 (d, J=11.2 Hz, 1H), 3.63 (d, J=8.8 Hz,1H), 3.46 (d, J=21.0 Hz, 7H), 3.14 (t, J=11.0 Hz, 1H), 1.20 (d, J=6.7Hz, 3H); MS (ES⁺) C₁₉H₂₄N₆O₃S requires: 416, found: 417 [M+H]⁺.

EXAMPLE 26

(R)-((2-(3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone

(R)-((2-(3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A microwave vial was charged with Int. V (150 mg, 0.268 mmol), Int. M(170 mg, 0.35 mmol), LiCl (23 mg, 0.54 mmol), CuI (5 mg, 0.027 mmol),Pd(PPh₃)₄ (31 mg, 0.027 mmol) and DMF (2 mL). The reaction vial wasdegassed by bubbling Ar into it the solution, sealed and heated to 120°C. for 90 min. a microwave reactor. The reaction was resubmitted to themicrowave cycle until it was judged completed by LCMS with new palladiumcatalyst added and the reaction vial degassed with Ar prior to eachcycle. The reaction mixture was diluted with EtOAc (20 mL), filteredthrough CELITE®, and concentrated under reduced pressure. The residuewas taken up in a 1 N HCl (10 mL) and washed with Et₂O (5 mL) andhexanes (5 mL). The aqueous layer was then adjusted to pH >12 with 2 Maq. NaOH and extracted with CH₂Cl₂ (3×5 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by reverse phase chromatography(Mobile phase: A=0.1% HCO₂H/H₂O, B=0.1% HCO₂H/MeCN; Gradient: B=0-30%;15 min; Column: Biotage SNAP Ultra C18 30 g, HP-Sphere C18 25 μm). Thecombined fractions were treated with 0.1 M aq. HCl, concentrated underreduced pressure and lyophilized to afford the titled compound (33.2 mg,32% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.71 (d, J=5.27 Hz, 1H) 8.52 (s, 1H) 8.16(d, J=5.02 Hz, 1H) 5.91 (s, 1H) 4.36-4.52 (m, 1H) 4.13-4.25 (m, 1H) 4.08(br dd, J=11.54, 3.76 Hz, 1H) 3.82-3.91 (m, 1H) 3.79 (br d, J=2.76 Hz,1H) 3.64 (br d, J=3.01 Hz, 1H) 3.46-3.52 (m, 1H) 3.43 (s, 6H) 3.29-3.39(m, 1H) 1.37 (d, J=6.78 Hz, 3H); MS (ES⁺) C₁₇H₂₁N₇O₂S requires: 387,found: 388 [M+H]⁺.

EXAMPLE 27

(R)-((2-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanoneStep 1

(R)-((2-(2-cyclopropyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A mixture of Int. U (50 mg, 0.13 mmol), Int. V (72 mg, 0.13 mmol), CuI(2 mg, 0.013 mmol), LiCl (3 mg, 0.26 mmol), Pd(PPh₃)₄ (15 mg, 0.013mmol) and DMF (5 mL) was degassed with Ar (3×) and then heated at 120°C. for 2 h in a microwave reactor. The mixture was cooled to RT, sat.aq. Na₂S₂O₃ (10 mL) was added, the layers were separated and the aqueouslayer was extracted with EtOAc (10 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified via silica gel chromatography (0-10%EtOAc in hexanes) to afford the title compound (30 mg, 40% yield) as ayellow solid.

MS (ES⁺) C₂₈H₃₂N₆O₄S₂ requires: 580, found: 581 [M+H]⁺.

Step 2

(R)-((2-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A mixture of the product from the previous step (30 mg, 0.05 mmol), NaOH(4 mg, 0.1 mmol), H₂O (1 mL) and MeOH (3 mL) was heated at 60° C. andstirred for 2 h. The mixture was cooled to RT and concentrated underreduced pressure. The residue was purified by reverse phase preparativeHPLC (Mobile phase: A=10 mM NH₄HCO₃/H₂O, B=MeCN; Gradient: B=45-75; 15min; Column: Welch XB-C18, 10 μm, 21.2×250 mm) to afford the titlecompound (2 mg, 10% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 11.58 (s, 1H), 8.14 (d, J=5.0 Hz, 1H), 7.80(d, J=5.0 Hz, 1H), 7.11 (s, 1H), 5.88 (s, 1H), 4.44 (s, 1H), 4.04 (d,J=12.9 Hz, 1H), 3.95 (d, J=10.9 Hz, 1H), 3.74 (d, J=11.4 Hz, 1H), 3.63(d, J=8.2 Hz, 1H), 3.46 (d, J=25.8 Hz, 7H), 2.03 (s, 1H), 1.20 (d, J=6.7Hz, 3H), 1.06-0.97 (m, 2H), 0.86 (d, J=3.0 Hz, 2H); MS (ES⁺) C₂₁H₂₆N₆O₂Srequires: 426, found: 427 [M+H]⁺.

EXAMPLE 28

(R)-dimethyl((2-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanoneStep 1

(R)-((2-(2,3-diaminopyridin-4-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A microwave vial was charged with Int. J (450 mg crude, assumed 1.07mmol), Int. D (250 mg, 0.82 mmol), Na₂CO₃ (260 mg, 2.46 mmol),Pd(dppf)Cl₂ (48 mg, 0.06 mmol), dioxane (12 mL) and H₂O (4 mL). The vialwas purged with N₂ and sealed. The reaction mixture was heated at 80° C.and stirred for 3 h. The reaction mixture was cooled to RT, filteredthrough CELITE®, and concentrated under reduced pressure. The residuewas purified via silica gel chromatography (0-15% MeOH in CH₂Cl₂) toafford the title compound (350 mg, 100% yield) as a brown solid.

MS (ES⁺) C₁₆H₂₃N₇O₂S requires: 377, found: 378 [M+H]⁺.

Step 2

(R)-dimethyl((2-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-6-(3-methyl-morpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone:A mixture of the product from the previous step (150 mg, 0.4 mmol), HOAc(0.2 mL) and PPA (1 g) were charged in a 20 mL microwave vial and purgedwith N₂ for 1 min. The vial was sealed and heated at 150° C. for 1.5 h.The reaction mixture was cooled to RT, sat. aq. K₂CO₃ (30 mL) was addedand the aqueous layer was extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by reverse phase preparative HPLC (Mobile phase: A=10 mMNH₄HCO₃/H₂O, B═MeCN; Gradient: B=25-55%; 18 min; Column: Welch XB-C18,10 μm, 150 Å, 21.2 mm×250 mm) to afford the title compound (20 mg, 12%yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 11.99 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 7.89(d, J=5.1 Hz, 1H), 5.97 (s, 1H), 4.47 (s, 1H), 4.14 (s, 1H), 3.95 (d,J=11.1 Hz, 1H), 3.74 (d, J=11.5 Hz, 1H), 3.63 (d, J=8.3 Hz, 1H), 3.47(s, 7H), 3.19-3.11 (m, 1H), 2.58 (s, 3H), 1.20 (d, J=6.7 Hz, 3H); MS(ES⁺) C₁₈H₂₃N₇O₂S requires: 401, found: 402 [M+H]⁺.

EXAMPLE 29

(R)-((2-(2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone

(R)-((2-(2-cyclopropyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A reaction vial was charged with Int. D (120 mg, 0.39 mmol),2-cyclopropyl-1H-benzo[d]imidazole (94 mg, 0.59 mmol), Pd₂dba₃ (18 mg,0.02 mmol), XPhos (16 mg, 0.04 mmol), Cs₂CO₃ (380 mg, 1.17 mmol) anddioxane (6 mL). The vial was purged with N₂ for 2 min., sealed andheated to 150° C. for 1 h in a microwave reactor. The reaction mixturewas cooled to RT, filtered through CELITE®, and concentrated underreduced pressure. The residue was purified by reverse phase preparativeHPLC (Mobile phase: A=10 mM NH₄HCO₃/H₂O, B=MeCN; Gradient: B=40-70%; 15min; Column: Agela C18, 10 μm, 150 Å, 21.2 mm×250 mm) to afford thetitle compound (83.0 mg, 50% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 8.10 (dd, J=6.8, 2.3 Hz, 1H), 7.53 (dd,J=6.5, 2.2 Hz, 1H), 7.24-7.14 (m, 2H), 5.93 (s, 1H), 4.36 (s, 1H), 3.94(dd, J=16.4, 8.5 Hz, 2H), 3.72 (d, J=11.4 Hz, 1H), 3.61 (dd, J=11.4, 2.9Hz, 1H), 3.50-3.44 (m, 1H), 3.42 (s, 6H), 3.17 (td, J=13.0, 3.9 Hz, 1H),3.09-3.01 (m, 1H), 1.21 (d, J=6.7 Hz, 3H), 1.17-1.11 (m, 2H), 1.09-1.02(m, 2H); MS (ES⁺) C₁₈H₂₂N₆O₂S requires: 426, found: 427 [M+H]⁺.

EXAMPLE 30

(R)-dimethyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone

(R)-dimethyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)-λ⁶-sulfanone:A microwave vial was charged with Int. D (50 mg, 0.165 mmol),2-methylbenzimidazole (44 mg, 0.329 mmol), XPhos Pd G2 (6.5 mg, 0.008mmol) and K₃PO₄ (70 mg, 0.329 mmol). The vial was sealed, purged withAr, dioxane (2 mL) was added and the solution was degassed by bubblingAr and the resulting mixture was heated in at 150° C. for 1 h in amicrowave reactor. The reaction mixture was cooled to RT, filteredthrough CELITE®, washed with CH₂Cl₂ and concentrated under reducedpressure. The residue was purified by flash chromatography (1-5% MeOH inCH₂Cl₂) to afford the title compound (62 mg, 94% yield) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.22-8.39 (m, 1H) 7.63-7.89 (m, 1H)7.30-7.54 (m, 2H) 5.86 (s, 1H) 4.25-4.41 (m, 1H) 4.05 (dd, J=11.54, 3.76Hz, 1H) 3.90-3.98 (m, 1H) 3.70-3.89 (m, 2H) 3.53-3.68 (m, 1H) 3.26-3.51(m, 7H) 3.06 (s, 3H) 1.36 (d, J=6.78 HZ, 3H) 1.10-1.32 (M, 1H) 0.91 (S,1H); MS (ES⁺) C₁₉H₂₄N₆O₂S REQUIRES: 400, FOUND: 401 [M+H]⁺.

EXAMPLE 31

Cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone

Synthesis is similar to that described for Example 11, using Int. I.

¹H NMR (500 MHz, DMSO-d₆) δ 11.72 (s, 1H), 9.02 (d, J=2.3 Hz, 1H), 8.79(s, 1H), 7.67 (t, J=2.7 Hz, 1H), 7.45 (s, 1H), 5.90 (s, 1H), 4.46 (s,1H), 4.04 (s, 1H), 3.96 (d, J=7.8 Hz, 1H), 3.75 (d, J=11.4 Hz, 1H), 3.64(d, J=10.5 Hz, 1H), 3.51 (dd, J=32.0, 6.9 Hz, 4H), 3.14 (s, 1H), 3.01(d, J=7.6 Hz, 1H), 1.21 (t, J=7.1 Hz, 5H), 1.09 (d, J=7.8 Hz, 2H); MS(ES⁺) C₂₀H₂₄N₆O₂S requires: 412, found: 413 [M+H]⁺.

EXAMPLE 32

(S)-((6-(3-(fluoromethyl)morpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone

Synthesis is similar to that described for Example 11, using Int. O and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine.

¹H NMR (400 MHz, CDCl₃) δ 10.35 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.01(d, J=5.1 Hz, 1H), 7.61-7.41 (m, 2H), 5.94 (s, 1H), 5.26-5.02 (m, 1H),4.53 (s, 1H), 4.31-3.96 (m, 3H), 3.83-3.61 (m, 4H), 3.44 (d, J=4.8 Hz,6H); MS (ES⁺) C₁₈H₂₁FN₆O₂S requires: 404, found: 405 [M+H]⁺.

EXAMPLE 33

(S)-((6-(3-(difluoromethyl)morpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone

Synthesis is similar to that described for Example 11, using Int. W and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine.

¹H NMR (400 MHz, Methanol-d4) δ 8.28 (d, J=5.1 Hz, 1H), 7.99 (d, J=5.2Hz, 1H), 7.51 (dd, J=21.8, 3.5 Hz, 2H), 6.34 (td, J=56.1, 5.7 Hz, 1H),6.06 (s, 1H), 4.25 (d, J=12.3 Hz, 1H), 4.06 (dd, J=11.4, 3.6 Hz, 2H),3.78 (dd, J=12.3, 3.2 Hz, 1H), 3.67 (td, J=11.8, 3.1 Hz, 1H), 3.49 (t,J=7.2 Hz, 7H), 3.43 (dd, J=12.7, 3.8 Hz, 1H), 3.34 (s, 2H), 3.32 (s,2H); MS (ES⁺) C₁₈H₂₀F₂N₆O₂S requires: 422, found: 423 [M+H]⁺.

EXAMPLE 34

(R)-((2-(4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanoneStep 1

(R)-((2-((3-fluoro-2-nitrophenyl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanoneA reaction vial was charged with Int. D (250 mg, 0.82 mmol),3-fluoro-2-nitroaniline (192 mg, 1.23 mmol), Pd₂dba₃ (38 mg, 0.041mmol), XPhos (35 mg, 0.082 mmol), Cs₂CO₃ (800 mg, 2.47 mmol) and dioxane(10 mL). The vial was purged with N₂ for 2 min. and the reaction mixturewas heated at 100° C. and stirred for 16 h. The reaction mixture wascooled to RT, filtered through CELITE® and concentrated under reducedpressure. The residue was purified via silica gel chromatography (50-75%EtOAc in hexanes) to afford the title compound (290 mg, 74% yield) as anorange solid.

MS (ES⁺) C₁₇H₂₁FN₆O₄S requires: 424, found: 425 [M+H]⁺.

Step 2

(R)-((2-((2-amino-3-fluorophenyl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A reaction vessel was charged with the product from the previous step(280 mg, 0.66 mmol), 10% Pd/C (50 mg, 0.047 mmol) and EtOH (40 mL) underan atmosphere of N₂. The suspension was degassed with N₂ for 1 minuteand purged with H₂ for 1 minute. The reaction mixture was stirred underan atmosphere of H₂ at 1 atm for 2 h. The reaction mixture was purgedwith N₂, filtered through CELITE® and concentrated under reducedpressure to afford the title compound (260 mg, quantitative yield) as ared solid.

MS (ES⁺) C₁₇H₂₃FN₆O₂S requires: 394, found: 395 [M+H]⁺.

Step 3

(R)-((2-(4-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanoneA mixture of the product from the previous step (260 mg, 0.66 mmol) andacetic acid (132 mg, 2.21 mmol) in PPA (5 g) was heated at 150° C. for 3h. The reaction was cooled to RT, diluted with water (50 mL) and 5 N aq.NaOH was added to adjust to pH=14. The aqueous layer was extracted withEtOAc (3×50 mL) and the combined organic layers were concentrated underreduced pressure. The residue was purified by reverse phase preparativeHPLC (Mobile phase: A=10 mM NH₄HCO₃ in water, B=MeCN; Gradient:B=35-65%; 15 min; Column: Agela C18, 10 μm, 150 Å, 21.2 mm×250 mm) toafford the title compound (146 mg, 53% yield) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ 8.10 (d, J=8.2 Hz, 1H), 7.19 (td, J=8.2, 5.1Hz, 1H), 7.06 (dd, J=10.6, 8.1 Hz, 1H), 5.92 (s, 1H), 4.35 (s, 1H),4.03-3.85 (m, 2H), 3.72 (d, J=11.4 Hz, 1H), 3.61 (dd, J=11.4, 2.9 Hz,1H), 3.47 (td, J=11.9, 3.0 Hz, 1H), 3.40 (d, J=2.1 Hz, 6H), 3.17 (td,J=12.9, 3.8 Hz, 1H), 2.85 (s, 3H), 1.21 (d, J=6.7 Hz, 3H); MS (ES⁺)C₁₉H₂₃FN₆O₂S requires: 418, found: 419 [M+H]⁺.

EXAMPLE 35

(R)-1-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-1H-benzo[d]imidazole-6-carbonitrileStep 1

(R)-4-amino-3-((4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methyl-morpholino)pyrimidin-2-yl)amino)benzonitrile:To a solution of(R)-3-((4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)amino)-4-nitrobenzonitrile(synthesis is similar to that described for Example 34, step 1) (110 mg,0.255 mmol) in EtOH (1.3 mL) were added ammonium chloride (54.5 mg, 1.02mmol), water (425 μL), and iron (56.9 mg, 1.02 mmol) and the resultingmixture was stirred at 100° C. for 3 h. The reaction mixture was cooledto RT, filtered through CELITE® and concentrated under reduced pressure.The residue was purified via silica gel chromatography (5-20% MeOH inCH₂Cl₂) to afford the title compound (83 mg, 81% yield) as a yellowsolid.

MS (ES⁺) C₁₈H₂₃N₇O₂S requires: 401, found: 402 [M+H]⁺.

Step 2

(R)-1-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)-pyrimidin-2-yl)-1H-benzo[d]imidazole-6-carbonitrile:To a solution of the product from the previous step (30 mg, 0.037 mmol)in toluene (75 μL) were added triethyl orthoformate (12 μL, 0.075 mmol)and Ts-OH hydrate (0.71 mg, 3.7 μmol) and the resulting mixture washeated at 110° C. and stirred for 16 h. The reaction mixture was cooledto RT and concentrated under reduced pressure. The residue was purifiedby mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=10-40%; 16 min; Column: XBridge C18, 5 μm, 19mm×150 mm) to afford the title compound (7.9 mg, 33% yield) as a whitesolid.

¹H NMR (600 MHz, Methanol-d4) δ 9.36 (s, 1H), 9.25-9.22 (m, 1H), 7.87(d, J=8.4 Hz, 1H), 7.69 (dd, J=8.4, 1.6 Hz, 1H), 5.91 (s, 1H), 4.47-4.39(m, 1H), 4.08-3.98 (m, 2H), 3.82 (d, J=11.5 Hz, 1H), 3.75 (dd, J=11.5,3.2 Hz, 1H), 3.60 (td, J=12.0, 3.2 Hz, 1H), 3.46 (s, 6H), 3.33-3.27 (m,overlap MeOH, 1H), 1.33 (d, J=6.8 Hz, 3H); MS (ES⁺) C₁₉H₂₁N₇O₂Srequires: 411, found: 412 [M+H]⁺.

EXAMPLE 36

(R)-dimethyl((2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone

(R)-dimethyl((2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone:To a suspension of(R)-((2-((2-aminopyridin-3-yl)amino)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone(synthesis is similar to that described for Example 34, step 2) (38 mg,0.10 mmol) in triethyl orthoacetate (4 mL) was added p-toluenesulfonicacid monohydrate (10 mg, 0.05 mmol) and the resulting mixture was heatedto 50° C. for 16 h. The reaction mixture was cooled to RT and directlypurified by flash chromatography (0-10% MeOH in CH₂Cl₂ with 0.5% of aq.NH₄OH) to afford the title compound (20 mg, 0.05 mmol) as a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.63-8.83 (m, 1H) 8.52 (dd, J=4.77, 1.25Hz, 1H) 7.20-7.34 (m, 2H) 5.82 (s, 1H) 4.17-4.39 (m, 1H) 4.04 (dd,J=11.54, 3.51 Hz, 1H) 3.91 (br d, J=12.30 Hz, 1H) 3.82 (d, J=11.54 Hz,1H) 3.73 (dd, J=11.54, 3.01 Hz, 1H) 3.59 (td, J=11.86, 3.14 Hz, 1H)3.27-3.45 (m, 7H) 3.04 (s, 3H) 1.34 (d, J=7.03 Hz, 3H); MS (ES⁺)C₁₈H₂₃N₇O₂S requires: 401, found: 402 [M+H]⁺.

EXAMPLE 37

((2-(2-Aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ⁶-sulfanoneStep 1

((2-Chloro-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ⁶-sulfanone:To a solution of (R)-4-(2,6-dichloropyrimidin-4-yl)-3-methylmorpholine(synthesized as described, Int. B, step 1) (4.6 g, 18.5 mmol) and Int. F(2.5 g, 18.5 mmol) in dioxane (80 mL) was added Pd₂(dba)₃ (850 mg, 0.925mmol), XantPhos (2.14 g, 3.7 mmol) and K₂CO₃(6.4 g, 46 mmol) under anatmosphere of N₂ and the resulting mixture was heated at 90° C. andstirred for 4 h. The reaction mixture was cooled to RT, filtered throughCELITE® and concentrated under reduced pressure. The residue waspurified via silica gel chromatography (25-70% EtOAc in hexanes) toafford the title compound (1.8 g, 28% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 5.86 (s, 1H), 5.07-4.74 (m, 5H), 4.23 (s,1H), 3.87 (dd, J=11.3, 3.5 Hz, 2H), 3.65 (d, J=11.5 Hz, 1H), 3.53 (dd,J=11.5, 2.9 Hz, 1H), 3.43-3.31 (m, 4H), 3.05 (d, J=3.6 Hz, 1H), 1.12 (d,J=6.7 Hz, 3H); MS (ES⁺) C₁₃H₁₉CN₄O₃S requires: 346, found: 347 [M+H]⁺.

Step 2

((2-(2-Aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-(methyl)(oxetan-3-yl)-λ⁶-sulfanone:To a solution of the product from the previous step (120 mg, 0.34 mmol)and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (61mg, 0.51 mmol) in dioxane (4 mL) and H₂O (1 mL) were added Pd(dppf)Cl₂(25 mg, 0.034 mmol) and K₂CO₃ (141 mg, 1.02 mmol) under an atmosphere ofN₂ and the resulting mixture was heated at 90° C. and stirred for 16 h.The reaction mixture was cooled to RT, filtered through CELITE® andconcentrated under reduced pressure. The residue was purified by reversephase preparative HPLC (Mobile phase: A=10 mM NH₄HCO₃/H₂O, B=MeCN;Gradient: B=20-50%; 18 min; Column: Agela C18, 10 μm, 150 Å, 21.2 mm×250mm) to afford the title compound (42 mg, 31% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (d, J=5.2 Hz, 1H), 7.50-7.03 (m, 2H),5.97 (d, J=58.0 Hz, 3H), 5.10-4.75 (m, 5H), 4.49-4.26 (m, 1H), 4.15-3.97(m, 1H), 3.95-3.88 (m, 1H), 3.71 (d, J=11.3 Hz, 1H), 3.60 (dd, J=11.4,2.8 Hz, 1H), 3.52 (d, J=2.0 Hz, 3H), 3.45 (s, 1H), 3.10 (d, J=3.5 Hz,1H), 1.16 (d, J=6.7 Hz, 3H); MS (ES⁺) C₁₈H₂₄N₆O₃S requires: 404, found:405 [M+H]⁺.

EXAMPLES 38a and 38b

(R)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ⁶-sulfanoneand

(S)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ⁶-sulfanone

Synthesis is similar to that described for Example 29, using theintermediate from the first step of the Example 37 procedure. Themixture of diastereomers (56 mg, 0.13 mmol) was separated by Chiral SFC(Mobile phase: CO₂/MeOH (0.2% MeOH Ammonia)=55/45; Flow rate: 80 g/min;6.3 min; Column temperature: 35° C.; Back pressure: 100 bar; Column:Daicel CHIRALPAK® OJ, 10 μm, 20 mm×250 mm) to afford the twodiastereomers of unknown absolute stereochemistry at the sulfur atom,title compounds 38a (14 mg, 25% yield, >99% ee) as a white solid and 38b(15 mg, 27% yield, >99% ee) as a white solid.

38a ((R)-methyl(oxetan-3-yl)-λ⁶-sulfanone or(S)-methyl(oxetan-3-yl)-λ⁶-sulfanone): ¹H NMR (500 MHz, DMSO-d₆) δ9.09-8.93 (m, 1H), 8.68-8.50 (m, 1H), 7.81-7.66 (m, 1H), 7.44-7.25 (m,2H), 5.96-5.86 (m, 1H), 5.06 (dd, J=7.0, 1.1 Hz, 1H), 5.00-4.84 (m, 4H),4.53-4.36 (m, 1H), 4.12-4.00 (m, 1H), 3.99-3.90 (m, 1H), 3.76-3.70 (m,1H), 3.68-3.58 (m, 1H), 3.50 (dd, J=19.4, 1.5 Hz, 4H), 3.18 (d, J=3.6Hz, 1H), 1.24-1.18 (m, 3H); MS (ES⁺) C₂₀H₂₄N₆O₃S requires: 428, found:429 [M+H]⁺; R_(t)=0.95 min.

38b ((R)-methyl(oxetan-3-yl)-λ⁶-sulfanone or(S)-methyl(oxetan-3-yl)-λ⁶-sulfanone): ¹H NMR (500 MHz, DMSO-d₆) δ 9.02(s, 1H), 8.60 (d, J=8.0 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.49-7.20 (m,2H), 5.92 (s, 1H), 5.11-5.01 (m, 1H), 4.99-4.85 (m, 4H), 4.47-4.39 (m,1H), 4.15-4.02 (m, 1H), 3.99-3.91 (m, 1H), 3.72 (s, 1H), 3.66-3.59 (m,1H), 3.51 (s, 4H), 3.23-3.11 (m, 1H), 1.22 (d, J=6.7 Hz, 3H); MS (ES⁺)C₂H₂₄N₆O₃S requires: 428, found: 429 [M+H]⁺; R_(t)=1.31 min.

EXAMPLES 39a and 39b

(R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanoneand

(S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone

Synthesis is similar to that described for Example 24. The mixture ofdiastereomers (26.8 mg, 0.069 mmol) was separated by Chiral SFC (Mobilephase: n-hexane (0.1% DEA):EtOH (0.1% DEA)=70:30; Flow rate: 80 g/min;20 min; Column temperature: 35° C.; Back pressure: 100 bar; Column:Gilson-281, AY 20×250 mm, 10 μm) to afford the two diastereomers ofunknown absolute stereochemistry at the sulfur atom, title compounds 39a(6.6 mg, 25% yield, >99% ee) as a white solid and 39b (7.1 mg, 27%yield, >99% ee) as a white solid.

39a ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (500 MHz, CD₃OD) δ8.03-7.91 (m, 1H), 7.53 (s, 1H), 7.49 (dd, J=5.5, 1.4 Hz, 1H), 5.97 (s,1H), 4.48 (d, J=4.6 Hz, 1H), 4.11 (d, J=12.0 Hz, 1H), 4.02 (dd, J=11.3,3.6 Hz, 1H), 3.82 (d, J=11.4 Hz, 1H), 3.75 (dd, J=11.5, 3.0 Hz, 1H),3.65-3.56 (m, 4H), 3.25 (td, J=12.8, 3.8 Hz, 1H), 3.01 (td, J=7.9, 4.0Hz, 1H), 1.42 (dd, J=10.2, 5.4 Hz, 1H), 1.31 (dd, J=11.1, 6.2 Hz, 4H),1.20 (dt, J=11.3, 5.7 Hz, 2H); MS (ES⁺) C₁₈H₂₄N₆O₂S requires: 388,found: 389 [M+H]⁺; R_(t)=11.35 min.

39b ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (500 MHz, CD₃OD) δ 7.97(d, J=5.4 Hz, 1H), 7.53 (s, 1H), 7.49 (dd, J=5.5, 1.3 Hz, 1H), 5.97 (s,1H), 4.50 (s, 1H), 4.08 (d, J=12.7 Hz, 1H), 4.02 (dd, J=11.4, 3.7 Hz,1H), 3.82 (d, J=11.3 Hz, 1H), 3.75 (dd, J=11.4, 3.0 Hz, 1H), 3.66-3.55(m, 4H), 3.25 (td, J=12.9, 3.9 Hz, 1H), 3.05-2.97 (m, 1H), 1.41 (dd,J=10.6, 5.2 Hz, 1H), 1.31 (dd, J=11.8, 5.8 Hz, 4H), 1.20 (dt, J=11.1,5.6 Hz, 2H); MS (ES⁺) C₁₈H₂₄N₆O₂S requires: 388, found: 389 [M+H]⁺;R_(t)=15.22 min.

Alternatively, Example 39a can also be prepared from Int. CC, Isomer 1b.

EXAMPLES 40a and 40b

(R)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanoneand

(S)-((2-(1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone

Synthesis is similar to that described for Example 29. The mixture ofdiastereomers (31 mg, 0.075 mmol) was separated by Chiral SFC (Mobilephase: CO₂/MeOH (0.2% MeOH Ammonia)=50/50; Flow rate: 80 g/min; 10 min;Column temperature: 35° C.; Back pressure: 100 bar; Column: DaicelCHIRALPAK® OD, 10 μm, 20 mm×250 mm) to afford the two diastereomers ofunknown absolute stereochemistry at the sulfur atom, title compounds 40a(6.0 mg, 19% yield, >99% ee) as a white solid and 40b (5.0 mg, 16%yield, >98% ee) as a white solid.

40a ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (500 MHz, DMSO-d₆) δ 9.01(s, 1H), 8.60 (d, J=7.7 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.33 (dd,J=13.5, 7.5 Hz, 2H), 5.90 (s, 1H), 4.53-4.29 (m, 1H), 3.95 (d, J=7.7 Hz,2H), 3.74 (d, J=11.2 Hz, 1H), 3.63 (d, J=11.3 Hz, 1H), 3.50 (d, J=19.7Hz, 4H), 3.17 (s, 1H), 3.04 (s, 1H), 1.22 (d, J=6.7 Hz, 5H), 1.13 (d,J=19.3 Hz, 2H); MS (ES⁺) C₂H₂₄N₆O₂S requires: 412, found: 413 [M+H]⁺;R_(t)=3.50 min.

40b ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (500 MHz, DMSO-d₆) δ 9.01(s, 1H), 8.60 (d, J=7.7 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.33 (ddd,J=15.1, 13.9, 6.7 Hz, 2H), 5.90 (s, 1H), 4.42 (s, 1H), 4.04 (s, 1H),3.95 (dd, J=11.3, 3.4 Hz, 1H), 3.74 (d, J=11.4 Hz, 1H), 3.63 (dd,J=11.5, 2.9 Hz, 1H), 3.55-3.45 (m, 4H), 3.22-3.14 (m, 1H), 3.10-3.01 (m,1H), 1.28-1.18 (m, 5H), 1.17-1.07 (m, 2H); MS (ES⁺) C₂₀H₂₄N₆O₂Srequires: 412, found: 413 [M+H]⁺; Rt=4.44 min.

Alternatively, Example 40b can also be prepared from Int. CC, Isomer 1b.

EXAMPLES 41a and 41b

(R)-methyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(oxetan-3-yl)-λ⁶-sulfanoneand

(S)-methyl((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(oxetan-3-yl)-λ⁶-sulfanone

Synthesis is similar to that described for Example 29. The mixture ofdiastereomers (45 mg, 0.1 mmol) was separated by Chiral SFC (Mobilephase: n-Hexane (0.1% DEA): IPA (0.1% DEA)=35:65; Flow rate: 80 g/min;20 min; Column temperature: 35° C.; Back pressure: 100 bar; Column:Gilson-281, sc 20×250 mm, 10 μm) to afford the two diastereomers ofunknown absolute stereochemistry at the sulfur atom, title compounds 41a(7.0 mg, 16% yield, 99% ee) as a white solid and 41b (4.0 mg, 9.0%yield, >93% ee) as a white solid.

41a ((R)-methyl(oxetan-3-yl)-λ⁶-sulfanone or(S)-methyl(oxetan-3-yl)-λ⁶-sulfanone): ¹H NMR (500 MHz, DMSO-d₆) δ 8.24(dd, J=6.1, 3.1 Hz, 1H), 7.58 (dd, J=6.0, 3.0 Hz, 1H), 7.29-7.15 (m,2H), 6.02-5.86 (m, 1H), 4.89 (dddd, J=17.8, 15.5, 7.8, 6.8 Hz, 5H), 4.40(s, 1H), 3.92 (d, J=11.3 Hz, 2H), 3.72 (d, J=11.4 Hz, 1H), 3.65-3.55 (m,1H), 3.44 (dd, J=15.6, 5.9 Hz, 4H), 3.22-3.12 (m, 1H), 2.88-2.77 (m,3H), 1.29-1.12 (m, 3H); MS (ES⁺) C₂₁H₂₆N₆O₃S requires: 442, found: 443[M+H]⁺; R_(t)=13.15 min.

41b ((R)-methyl(oxetan-3-yl)-λ⁶-sulfanone or(S)-methyl(oxetan-3-yl)-λ⁶-sulfanone): ¹H NMR (500 MHz, DMSO-d₆) δ8.30-8.15 (m, 1H), 7.66-7.51 (m, 1H), 7.23 (dd, J=6.0, 3.2 Hz, 2H), 5.95(s, 1H), 4.84 (s, 5H), 4.41-4.30 (m, 1H), 4.03-3.88 (m, 2H), 3.75-3.67(m, 1H), 3.64-3.58 (m, 1H), 3.42 (s, 4H), 3.23-3.12 (m, 1H), 2.83 (s,3H), 1.20 (d, J=6.7 Hz, 3H); MS (ES⁺) C₂₁H₂₆N₆O₃S requires: 442, found:443[M+H]⁺; R_(t)=17.06 min.

EXAMPLES 42a and 42b

(R)-((2-(2-amino-6-chloropyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanoneand

(S)-((2-(2-amino-6-chloropyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(cyclopropyl)(methyl)-λ⁶-sulfanone

Synthesis is similar to that described for Example 24. The mixture ofdiastereomers (100 mg, 0.18 mmol) was separated by Chiral SFC (Mobilephase: CO₂/ethanol (1% MeOH Ammonia)=40/60; Flow rate: 80 g/min; 12 min;Column temperature: 35° C.; Back pressure: 100 bar; Column: DaicelCHIRALPAK® OJ, 10 μm, 20 mm×250 mm) to afford the two diastereomers ofunknown absolute stereochemistry at the sulfur atom, title compounds 42a(13 mg, 20% yield, >99% ee) as a white solid and 42b (20 mg, 31% yield,96.7% ee) as a yellow solid.

42a ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (400 MHz, MeOD-d4) δ 7.41(s, 2H), 5.97 (s, 1H), 4.45 (s, 1H), 4.05 (dd, J=29.3, 11.7 Hz, 2H),3.82 (d, J=11.6 Hz, 1H), 3.74 (d, J=8.8 Hz, 1H), 3.63-3.55 (m, 4H),3.26-3.21 (m, 1H), 3.02-2.95 (m, 1H), 1.41 (s, 1H), 1.31 (dd, J=11.6,5.8 Hz, 4H), 1.20 (d, J=7.5 Hz, 2H); MS (ES⁺) C₁₈H₂₃ClN₆O₂S requires:422, found: 423 [M+H]⁺; R_(t)=4.27 min.

42b ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (400 MHz, MeOD-d4) δ 7.25(d, J=1.7 Hz, 2H), 5.88 (s, 1H), 4.36 (d, J=4.8 Hz, 1H), 4.00-3.86 (m,2H), 3.70 (d, J=11.5 Hz, 1H), 3.62 (dd, J=11.5, 2.8 Hz, 1H), 3.52-3.43(m, 4H), 3.18-3.10 (m, 1H), 2.92-2.83 (m, 1H), 1.31 (dd, J=11.3, 5.6 Hz,1H), 1.22-1.17 (m, 4H), 1.09 (dd, J=9.5, 5.3 Hz, 2H); MS (ES⁺)C₁₈H₂₃ClN₆O₂S requires: 422, found: 423 [M+H]⁺; Rt=5.48 min.

Alternatively, Example 42a can also be prepared from Int. CC, Isomer 1b.

EXAMPLES 43a and 43b

(R)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ⁶-sulfanoneand

(S)-((2-(2-aminopyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ⁶-sulfanone

Synthesis is similar to that described for Example 24. The mixture ofdiastereomers (36 mg, 0.089 mmol) was separated by Chiral SFC (Mobilephase: n-Hexane (0.1% DEA): EtOH (0.1% DEA)=60:40; Flow rate: 80 g/min;17 min; Column temperature: 35° C.; Back pressure: 100 bar; Column:Gilson-281, AY 20*250 mm, 10 μm) to afford the two diastereomers ofunknown absolute stereochemistry at the sulfur atom, title compounds 43a(9.0 mg, 23% yield, >99% ee) as a white solid and 43b (7.0 mg, 19%yield, >98% ee) as a white solid.

43a ((R)-methyl(oxetan-3-yl)-λ⁶-sulfanone or(S)-methyl(oxetan-3-yl)-λ⁶-sulfanone): ¹H NMR (500 MHz, CD₃OD) δ 7.98(d, J=5.7 Hz, 1H), 7.59-7.37 (m, 2H), 5.99 (s, 1H), 5.12 (d, J=2.4 Hz,1H), 5.07-4.96 (m, 4H), 4.52-4.41 (m, 1H), 4.16-4.06 (m, 1H), 4.00 (d,J=3.7 Hz, 1H), 3.82 (d, J=11.4 Hz, 1H), 3.75 (d, J=3.0 Hz, 1H), 3.60 (d,J=2.9 Hz, 1H), 3.52 (s, 3H), 3.25 (d, J=4.1 Hz, 1H), 1.29 (d, J=6.8 Hz,3H); MS (ES⁺) C₁₈H₂₄N₆O₃S requires: 404, found: 405 [M+H]⁺; R_(t)=9.34min.

43b ((R)-methyl(oxetan-3-yl)-λ⁶-sulfanone or(S)-methyl(oxetan-3-yl)-λ⁶-sulfanone): ¹H NMR (500 MHz, CD₃OD) δ 7.86(d, J=5.6 Hz, 1H), 7.44-7.29 (m, 2H), 5.87 (s, 1H), 4.99 (d, J=2.5 Hz,1H), 4.89 (ddd, J=10.3, 7.5, 4.5 Hz, 4H), 4.40-4.32 (m, 1H), 4.02-3.85(m, 2H), 3.64 (dt, J=11.4, 7.2 Hz, 2H), 3.47 (d, J=2.9 Hz, 1H), 3.39 (s,3H), 3.16-3.07 (m, 1H), 1.17 (d, J=6.8 Hz, 3H); MS (ES⁺) C₁₈H₂₄N₆O₃Srequires: 404, found: 405 [M+H]⁺; R_(t)=12.75 min.

EXAMPLES 44a and 44b

(R)-cyclopropyl(methyl)((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanoneand

(S)-cyclopropyl(methyl)((2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone

Synthesis is similar to that described for Example 30. The mixture ofdiastereomers (33.8 mg, 0.08 mmol) was separated by Chiral SFC (Mobilephase: n-Hexane (0.1% DEA): EtOH (0.1% DEA)=75:25; Flow rate: 80 g/min;17 min; Column temperature: 35° C.; Back pressure: 100 bar; Column:Gilson-281, sc 20×250 mm, 10 μm) to afford the two diastereomers ofunknown absolute stereochemistry at the sulfur atom, title compounds 44a(5.0 mg, 15% yield, >99% ee) as a white solid and 44b (5.0 mg, 15%yield, >93% ee) as a white solid.

44a ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (500 MHz, CD₃OD) δ 8.32(dd, J=6.4, 2.9 Hz, 1H), 7.69-7.54 (m, 1H), 7.38-7.20 (m, 2H), 5.97 (s,1H), 4.45 (s, 1H), 4.07-3.91 (m, 2H), 3.85-3.72 (m, 2H), 3.67-3.56 (m,1H), 3.49 (s, 3H), 2.97-2.86 (m, 4H), 1.40 (dd, J=12.6, 10.1 Hz, 1H),1.35-1.25 (m, 5H), 1.18 (q, J=7.2 Hz, 2H); MS (ES⁺) C₂₁H₂₆N₆O₂Srequires: 426, found: 427 [M+H]⁺; R_(t)=12.98 min.

44b ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone): ¹H NMR (400 MHz, CD₃OD) δ 8.31(dd, J=6.5, 2.9 Hz, 1H), 7.67-7.51 (m, 1H), 7.29 (dd, J=6.1, 3.2 Hz,2H), 5.97 (s, 1H), 4.44-4.34 (m, 1H), 4.02 (d, J=11.4 Hz, 2H), 3.80 (dd,J=22.8, 7.2 Hz, 2H), 3.60 (s, 1H), 3.49 (s, 3H), 2.95-2.87 (m, 4H),1.43-1.29 (m, 6H), 1.21-1.12 (m, 2H); MS (ES⁺) C₂₁H₂₆N₆O₂S requires:426, found: 427 [M+H]⁺; R_(t)=16.31 min.

Alternatively, Example 44b can also be prepared from Int. CC, Isomer 1b.

EXAMPLES 45a and 45b

(R)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ⁶-sulfanoneand

(S)-((2-(2-amino-6-methoxypyridin-4-yl)-6-((R)-3-methylmorpholino)pyrimidin-4-yl)imino)(methyl)(oxetan-3-yl)-λ⁶-sulfanone

Synthesis is similar to that described for Example 17. The mixture ofdiastereomers (300 mg, 0.691 mmol) was separated by Chiral SFC (Mobilephase: CO₂, MeOH/CH₃CN (1:1) (0.25% i-PrNH₂)=65:35; Flow rate: 80 g/min;5 min; Column temperature: 25° C.; Back pressure: 100 bar; Column:Chiral Technologies Chiralcel OX-H, 21×250 mm) to afford the twodiastereomers of unknown absolute stereochemistry at the sulfur atom,title compounds 45a (94 mg, 31% yield, 95% ee) as a tan solid and 45b(125 mg, 42% yield, 96% ee) as a tan solid.

45a ((R)-methyl(oxetan-3-yl)-λ⁶-sulfanone or(S)-methyl(oxetan-3-yl)-λ⁶-sulfanone): ¹H NMR (600 MHz, DMSO-d₆) δ 6.85(s, 1H), 6.65 (s, 1H), 6.00 (s, 2H), 5.90 (s, 1H), 5.02-4.95 (m, 1H),4.95 (t, J=6.8 Hz, 1H), 4.90-4.83 (m, 3H), 4.39 (s, 1H), 4.04 (d, J=13.2Hz, 1H), 3.92 (d, J=11.5 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J=11.3 Hz, 1H),3.59 (d, J=11.3 Hz, 1H), 3.51 (s, 3H), 3.45 (t, J=12.0 Hz, 1H), 3.09 (t,J=12.9 Hz, 1H), 1.16 (d, J=6.7 Hz, 3H); MS (ES⁺) C₁₉H₂₆N₆O₄S requires:434, found: 435 [M+H]⁺; R_(t)=3.1 min.

45b ((R)-methyl(oxetan-3-yl)-λ⁶-sulfanone or(S)-methyl(oxetan-3-yl)-λ⁶-sulfanone): ¹H NMR (600 MHz, DMSO-d₆) δ 6.85(s, 1H), 6.65 (s, 1H), 6.01 (s, 2H), 5.90 (s, 1H), 4.97 (dt, J=22.9, 6.7Hz, 2H), 4.87 (d, J=8.1 Hz, 3H), 4.41 (s, 1H), 4.03 (d, J=13.3 Hz, 1H),3.92 (d, J=10.9 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J=11.4 Hz, 1H), 3.59 (d,J=11.4 Hz, 1H), 3.50 (s, 3H), 3.44 (t, J=11.9 Hz, 1H), 3.09 (t, J=12.3Hz, 1H), 1.16 (d, J=6.7 Hz, 3H); MS (ES⁺) C₁₉H₂₆N₆O₄S requires: 434,found: 435 [M+H]⁺; R_(t)=3.4 min.

EXAMPLES 46a and 46b

(R)-cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanoneand

(S)-cyclopropyl(methyl)((6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone

46a ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone); synthesized from Int. CC, Isomer1a similar to that as described for Example 10: (20 mg, 32% yield, >99%ee) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.30(d, J=5.0 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.60-7.51 (m, 1H), 7.41 (s,1H), 5.95 (s, 1H), 4.47 (s, 1H), 4.01 (dd, J=36.7, 10.5 Hz, 2H), 3.75(d, J=11.1 Hz, 1H), 3.64 (d, J=8.7 Hz, 1H), 3.57-3.44 (m, 4H), 3.15 (t,J=12.7 Hz, 1H), 3.00 (s, 1H), 1.21 (d, J=6.7 Hz, 5H), 1.14-1.01 (m, 2H);MS (ES⁺) C₂₀H₂₄N₆O₂S requires: 412, found: 413 [M+H]⁺; Rt=3.20 min.

46b ((R)-cyclopropyl(methyl)-λ⁶-sulfanone or(S)-cyclopropyl(methyl)-λ⁶-sulfanone); synthesized from Int. CC, Isomer1b similar to that as described for Example 10: ¹H NMR (400 MHz,DMSO-d6) δ 11.73 (s, 1H), 8.30 (d, J=5.0 Hz, 1H), 7.90 (d, J=5.0 Hz,1H), 7.59-7.48 (m, 1H), 7.44-7.28 (m, 1H), 5.95 (s, 1H), 4.45 (s, 1H),4.01 (dd, J=36.7, 10.5 Hz, 2H), 3.75 (d, J=11.5 Hz, 1H), 3.64 (d, J=9.4Hz, 1H), 3.55 (s, 3H), 3.48 (d, J=11.8 Hz, 1H), 3.16 (s, 1H), 3.02 (s,1H), 1.20 (d, J=6.7 Hz, 5H), 1.10 (s, 2H); MS (ES⁺) C₂H₂₄N₆O₂S requires:412, found: 413 [M+H]⁺; R_(t)=2.09 min.

EXAMPLE 47

(R)-((2-(1H-indol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone

(R)-((2-(1H-indol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:To a solution of indole (43 mg, 0.360 mmol) in DMF (0.75 mL) 0° C. wasadded NaH (60% wt., 16 mg, 0.394 mmol) and the resulting solution wasallowed to slowly warm up to RT and stirred over 15 min. The reactionmixture was added a solution of Int. D (100 mg, 0.328 mmol) in a DMF(0.75 mL) and the reaction mixture was heated to 100° C. and stirred for16 h. The reaction mixture was cooled to RT, partitioned between water(15 mL) and EtOAc (5 mL), the layers were separated and the aqueouslayer was extracted with EtOAc (3×5 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatography(5-100% EtOAc in hexanes) to afford the title compound (42 mg, 33%yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.77 (d, J=8.28 Hz, 1H) 8.20 (d, J=3.76Hz, 1H) 7.62 (d, J=8.03 Hz, 1H) 7.30-7.46 (m, 1H) 7.12-7.27 (m, 1H) 6.64(d, J=3.51 Hz, 1H) 5.75 (s, 1H) 4.38 (br d, J=8.28 Hz, 1H) 3.95-4.13 (m,2H) 3.83 (s, 1H) 3.80 (br d, J=3.01 Hz, 1H) 3.59-3.69 (m, 1H) 3.50 (d,J=7.03 Hz, 1H) 3.44 (s, 4H) 3.34 (s, 1H) 1.36 (d, J=7.03 Hz, 3H) 1.23(t, J=7.03 Hz, 1H) 0.91 (s, 1H); MS (ES⁺) C₁₉H₂₃N₅O₂S requires: 385,found: 386 [M+H]⁺.

EXAMPLE 48

(R)-dimethyl((2-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone

(R)-dimethyl((2-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)-λ⁶-sulfanonehydrochloride: A reaction vial was charged with Int. D (50 mg, 0.0165mmol), 2-methylimidazo[1,2-a]pyridine (33 mg, 0.25 mmol), Pd(OAc)₂ (1.8mg, 0.008 mmol), tricyclohexylphosphonium tetrafluoroborate (6.3 mg,0.017 mmol), pivalic acid (5.0 mg, 0.05 mmol) and K₂CO₃ (46 mg, 0.33mmol). The vial was sealed, purged with Ar, DMF (1 mL) was added and theresulting mixture was heated to 110° C. for 1 h. The reaction mixturewas cooled to RT, filtered through CELITE®, washed with CH₂Cl₂ andconcentrated under reduced pressure. The residue was purified by flashchromatography (0-10% MeOH in CH₂Cl₂) followed by reverse phasechromatography (Mobile phase: A=0.1% HCO₂H/H₂O, B=0.1% HCO₂H/MeCN;Gradient: B=5-50%; 15 min; Column: Biotage SNAP Ultra C18 30 g,HP-Sphere C18 25 μm). The combined fractions were treated with 0.1 M aq.HCl, concentrated under reduced pressure and lyophilized to afford thetitle compound (26 mg, 36% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.23 (dt, J=7.03, 1.00 Hz, 1H) 8.01 (d,J=1.00 Hz, 2H) 7.48-7.56 (m, 1H) 5.96 (s, 1H) 4.33-4.47 (m, 2H)3.91-3.99 (m, 3H) 3.70-3.81 (m, 2H) 3.60-3.69 (m, 1H) 3.45-3.54 (m, 1H)3.43 (s, 6H) 3.15 (br d, J=3.76 Hz, 1H) 2.90 (s, 3H) 1.13-1.30 (m, 4H);MS (ES⁺) C₁₉H₂₄N₆O₂S requires: 400, found: 401 [M+H]⁺.

EXAMPLE 49

(R)-6-amino-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinamideStep 1

(R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinicacid: To a solution of Int. BB (30 mg, 0.063 mmol) in THF (225 μL), MeOH(45.0 μL) and water (45.0 μL) was added LiOH (1.5 mg, 0.063 mmol) andthe resulting mixture was stirred at RT for 12 h. The mixture wasfiltered and concentrated under reduced pressure. The residue waspurified by mass-triggered preparative HPLC (Mobile phase: A=0.1%TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=20-50%; 20 min; Column: XBridgeC18, 5 μm, 19 mm×150 mm) to afford the title compound (15 mg, 0.026mmol, 41.3% yield) as a pale yellow solid.

MS (ES⁺) C₂₁H₃₀N₆O₄S requires: 462, found: 463 [M+H]⁺.

Step 2

(R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)picolinamide:To a solution of the product form the previous step (15 mg, 0.026 mmol)in acetonitrile (130 μL) were added ammonium bicarbonate (8.2 mg, 0.10mmol), EDC (9.97 mg, 0.052 mmol), HOBt hydrate (8.0 mg, 0.052 mmol) andDIPEA (14 μL, 0.078 mmol) and the resulting mixture was stirred at RTfor 2 h. The mixture was filtered through a Whatman™ syringe filter (13mm, 0.45 μm) and directly purified by mass-triggered preparative HPLC(Mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=20-50%; 16min; Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the titlecompound (12 mg, 80% yield) as a pale yellow solid.

MS (ES⁺) C₂₁H₃₁N₇O₃S requires: 461, found: 462 [M+H]⁺.

Step 3

(R)-6-amino-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methyl-morpholino)pyrimidin-2-yl)picolinamide:A solution of the product from the previous step (6.6 mg, 0.011 mmol) inTFA (57 μL) was stirred at 65° C. for 24 h. The mixture was cooled toRT, diluted with CH₂Cl₂ (2 mL) and concentrated under reduced pressure.The residue was purified by mass-triggered preparative HPLC (Mobilephase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min;Column: Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the titlecompound (4 mg, 55% yield) as a white solid.

¹H NMR (600 MHz, Methanol-d4) δ 8.10 (s, 1H), 7.81 (s, 1H), 6.11 (s,1H), 4.54 (s, 1H), 4.19 (s, 1H), 4.02 (dd, J=11.4, 3.7 Hz, 1H), 3.82 (d,J=11.6 Hz, 1H), 3.73 (dd, J=11.7, 3.1 Hz, 1H), 3.59 (td, J=12.0, 2.8 Hz,1H), 3.51 (s, 6H), 3.38-3.27 (m, overlap MeOH, 1H), 1.33 (d, J=6.9 Hz,3H); MS (ES⁺) C₁₇H₂₃N₇O₃S requires: 405, found: 406 [M+H]⁺.

EXAMPLE 50

(R)-6-amino-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-N-ethylpicolinamideStep 1

(R)-6-(tert-butylamino)-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methylmorpholino)pyrimidin-2-yl)-N-ethylpicolinamide:A mixture of Int. BB (30 mg, 0.063 mmol) and ethanamine (2.0 M in THF,629 μL, 1.26 mmol) was stirred at 65° C. for 16 h. Another aliquot ofethanamine (2.0 M THF, 629 μL, 1.259 mmol) was added and the mixture washeated at 65° C. for an additional 24 h. The mixture was cooled to RTand concentrated under reduced pressure. The residue was purified bymass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=30-70%; 20 min; Column: XBridge C18, 5 μm, 19mm×150 mm) to afford the title compound (15 mg, 49% yield) as a paleyellow solid.

MS (ES⁺) C₂₃H₃₅N₇O₃S requires: 489, found: 490 [M+H]⁺.

Step 2

(R)-6-amino-4-(4-((dimethyl(oxo)-λ⁶-sulfaneylidene)amino)-6-(3-methyl-morpholino)pyrimidin-2-yl)-N-ethylpicolinamide:A solution of the product from the previous step (10 mg, 0.020 mmol) inTFA (102 μL) was stirred at 65° C. for 24 h. The mixture was cooled toRT, diluted with CH₂Cl₂ (2 mL) and concentrated under reduced pressure.The residue was purified by mass-triggered preparative HPLC (Mobilephase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; Gradient: B=10-40%; 20 min;Column: XBridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (6mg, 44% yield) as a white solid.

¹H NMR (600 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.71 (s, 1H), 6.13 (s,1H), 4.56 (s, 1H), 4.21 (s, 1H), 4.03 (dd, J=11.7, 3.8 Hz, 1H), 3.83 (d,J=11.6 Hz, 1H), 3.73 (dd, J=11.6, 3.2 Hz, 1H), 3.59 (td, J=12.0, 2.4 Hz,2H), 3.51 (s, 6H), 3.46 (q, J=7.3 Hz, 2H), 3.39-3.32 (m, overlap MeOH,1H), 1.34 (d, J=6.8 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H); MS (ES⁺)C₁₉H₂₇N₇O₃S requires: 433, found: 434 [M+H]⁺.

EXAMPLE 51

(R)-dimethyl((6-(3-methylmorpholino)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone

(R)-dimethyl((6-(3-methylmorpholino)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone:A microwave reaction vial was charged with Int. D (0.10 g, 0.33 mmol),2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(0.10 g, 0.38 mmol), PdCl₂(dppf)-CH₂Cl₂ (0.030 g, 0.040 mmol) and K₃PO₄(0.22 g, 1.04 mmol) in dioxane (3 mL) and water (0.8 mL) and the mixturewas degassed with a stream of N₂ for five minutes. The vial was sealedand heated at 100° C. for 40 minutes in a microwave reactor. Thereaction mixture was cooled to RT, partitioned between EtOAc (20 mL) andbrine (20 mL), the layers were separated and the aqueous layer wasextracted EtOAc (2×20 mL). The combined organic layers were dried overMgSO⁴, filtered and concentrated under reduced pressure. The residue waspurified via silica gel chromatography (1-8% MeOH in CH₂Cl₂) to affordthe title compound (78 mg, 59% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.71 (d, J=8.78 Hz, 1H), 8.41 (d, J=6.78Hz, 1H), 7.19-7.35 (m, 1H), 6.79 (td, J=6.84, 1.38 Hz, 1H), 5.75 (s,1H), 4.32-4.50 (m, 1H), 3.91-4.14 (m, 2H), 3.74-3.90 (m, 2H), 3.57-3.70(m, 1H), 3.40 (d, J=7.78 Hz, 6H), 3.29 (td, J=12.74, 3.89 Hz, 1H), 2.87(s, 3H), 1.33 (d, J=6.78 Hz, 3H); MS (ES⁺) C₁₉H₂₄N₆O₂S requires: 400,found: 401 [M+H]⁺.

EXAMPLE 52

(R)-((2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone

(R)-((2-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:To a solution of(R)-dimethyl((6-(3-methylmorpholino)-2-(2-(((triisopropylsilyl)oxy)methyl)-1H-benzo[d]imidazol-1-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone(synthesis is similar to that described for Example 30, derived fromIntermed. FF) (0.081 g, 0.14 mmol) in THF (5 mL) was added HF pyridine,30% (HF ca. 70%, 1.3 mL) and the resulting mixture was stirred at RT for1 h. The reaction mixture was poured into sat. aq. NaHCO₃(50 mL) andstirred vigorously for 15 min. The layers were separated and the aqueouslayer was extracted with CH₂Cl₂ (2×50 mL). The combined organic layerswere dried over MgSO₄, filtered and concentrated under reduced pressure.The residue was purified via reverse phase C18 chromatography (10-100%MeCN in 0.1% TFA/H₂O). The combined fractions were made alkaline by theaddition of sat. aq. NaHCO₃and the aqueous layer was extracted withCH₂Cl₂ (2×50 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated under reduced pressure to afford the titlecompound (0.052 g, 88% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.32-8.50 (m, 1H), 7.63-7.80 (m, 1H),7.20-7.36 (m, 2H), 5.74 (s, 1H), 5.14 (s, 2H), 4.12-4.27 (m, 1H), 3.96(br dd, J=11.42, 3.64 Hz, 1H), 3.81 (br d, J=13.05 Hz, 1H), 3.61-3.77(m, 2H), 3.51 (td, J=11.92, 3.01 Hz, 1H), 3.19-3.36 (m, 8H), 1.27 (d,J=6.78 Hz, 3H); MS (ES⁺) C₁₉H₂₄N₆O₃S requires: 416, found: 417 [M+H]⁺.

EXAMPLE 53

(R)-((2-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone

(R)-((2-(2-(fluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)-pyrimidin-4-yl)imino)dimethyl-λ⁶-sulfanone:A mixture of Int. D (0.152 g, 0.499 mmol),2-(fluoromethyl)-1H-benzo[d]imidazole (0.090 g, 0.60 mmol), sodiumtert-butoxide (0.086 g, 0.90 mmol) and t-BuBrettPhos Palladacycle G3(0.021 g, 0.025 mmol) in dioxane (5 mL) was degassed with a stream of N₂for five minutes and the resulting mixture was heated to 80° C. for 18h. The reaction mixture was cooled to RT, filtered through CELITE® andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (10% CH₃CN in CH₂Cl₂) to afford the title compound(102 mg, 49% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.40 (d, J=8.03 Hz, 1H), 7.77 (br d,J=7.53 Hz, 1H), 7.23-7.46 (m, 2H), 5.85-6.16 (m, 2H), 5.74 (s, 1H), 4.22(br d, J=4.52 Hz, 1H), 3.80-4.02 (m, 2H), 3.60-3.79 (m, 2H), 3.52 (td,J=11.92, 3.01 Hz, 1H), 3.14-3.39 (m, 7H), 1.27 (d, J=6.78 Hz, 3H); MS(ES⁺) C₁₉H₂₃FN₆O₂S requires: 418, found: 419 [M+H]⁺.

EXAMPLE 54

(R)-dimethyl((2-(1-methyl-1H-imidazol-5-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone

(R)-dimethyl((2-(1-methyl-1H-imidazol-5-yl)-6-(3-methylmorpholino)pyrimidin-4-yl)imino)-λ⁶-sulfanone:A solution of Int. D (50 mg, 0.164 mmol),1-methyl-5-(tributylstannyl)-1H-imidazole (77 mg, 0.20 mmol) in toluene(820 μL) was degassed with N₂ for 1 minute. Pd(Ph₃P)₄ (19 mg, 0.016mmol) was added and the mixture was degassed with N₂ for an additional30 seconds, and the reaction mixture was heated at 110° C. for 16 h. Thereaction mixture was cooled to RT, filtered through CELITE®, washed withCH₂Cl₂ and concentrated under reduced pressure. The residue was purifiedby mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H₂O, B=0.1%TFA/MeCN; Gradient: B=0-30%; 20 min; Column: XBridge C18, 5 μm, 19mm×150 mm) to afford the title compound (5.4 mg, 6% yield) as a whitesolid.

¹H NMR (600 MHz, Methanol-d₄) δ 8.88 (s, 1H), 8.12 (s, 1H), 5.97 (s,1H), 4.42-4.36 (m, 1H), 4.28 (s, 3H), 4.03-3.94 (m, 2H), 3.80 (d, J=11.5Hz, 1H), 3.71 (dd, J 11.6, 3.2 Hz, 1H), 3.57 (td, J=11.9, 3.1 Hz, 1H),3.44 (s, 6H), 3.32-3.23 (n, overlap MeOH, 1H), 1.29 (d, J=6.8 Hz, 3H);MS (ES⁺) C₁₅H₂₂N₆O₂S requires: 350, found: 351 [M+H]⁺.

The compounds reported in Table 2 were synthesized using the methoddescribed for the previously disclosed Examples. The appropriatesulfoximines were prepared as described for Intermediates C.

TABLE 2 Example compounds 55-125. Ex. Ex Structure IUPAC Name MWt [M +H] Method 55

(R)-1-(1-((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]-pyridin-4-yl)pyrimidin-4- yl)imino)-1-oxido-1λ⁶- thiomorpholino)propan-1-one 483 484 12 56

Methyl (R)-1-((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]-pyridin-4-yl)pyrimidin-4- yl)imino)-1λ⁶- thiomorpholine-4- carboxylate1-oxide 485 486 12 57

(1-Acetylpiperidin-4-yl)- (methyl)((6-((R)-3- methylmorpholino)-2-(1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-λ⁶-sulfanone 497498 12 58

Methyl 4-(S-methyl-N- (6-((R)-3-methyl- morpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4- yl)pyrimidin-4-yl)- sulfonimidoyl)piperidine-1-carboxylate 513 514 12 59

Methyl((6-((R)-3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]-pyridin-4-yl)pyrimidin-4- yl)imino)(1-propionyl- piperidin-4-yl)-λ⁶-sulfanone 511 512 12 60

Methyl((6-((R)-3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]-pyridin-4-yl)pyrimidin-4- yl)imino)(oxetan-3-yl)- λ⁶-sulfanone 428 42912 61

(R)-cyclopropyl(1-((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]-pyridin-4-yl)pyrimidin-4- yl)imino)-1-oxido-1λ⁶- thiomorpholino)-methanone 495 496 12 62

(R)-2-methoxy-1-(1-((6- (3-methylmorpholino)-2- (1H-pyrrolo[2,3-b]-pyridin-4-yl)pyrimidin-4- yl)imino)-1-oxido-1λ⁶- thiomorpholino)ethan-1-one 499 500 12 63

Isopropyl (R)-1-((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]-pyridin-4-yl)pyrimidin-4- yl)imino)-1λ⁶- thiomorpholine-4- carboxylate1-oxide 513 514 12 64

Ethyl (R)-1-((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]-pyridin-4-yl)pyrimidin-4- yl)imino)-1λ⁶- thiomorpholine-4- carboxylate1-oxide 499 500 12 65

(R)-1-((6-(3-methyl- morpholino)-2-(1H- pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)imino)- 1λ⁶-thiomorpholine 1- oxide 427 428 12 66

(R)-((2-(2-aminopyridin- 4-yl)-6-(3-methyl- morpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶- sulfanone 362 363 24 67

(R)-2-hydroxy-1-(1-((6- (3-methylmorpholino)-2- (1H-pyrrolo[2,3-b]-pyridin-4-yl)pyrimidin-4- yl)imino)-1-oxido-1λ⁶- thiomorpholino)ethan-1-one 485 486 12 68

(R)-((2-(imidazo[1,2-a]- pyridin-5-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)- imino)dimethyl-λ⁶- sulfanone 386 387 25 69

(R)-dimethyl((6-(3- methylmorpholino)-2- (7H-pyrrolo[2,3-d]-pyrimidin-4-yl)- pyrimidin-4-yl)imino)- λ⁶-sulfanone 387 388 11 70

(R)-((2-(2-ethyl-1H- benzo[d]imidazol-1-yl)- 6-(3-methyl-morpholino)pyrimidin-4- yl)imino)dimethyl-λ⁶- sulfanone 414 415 30 71

(R)-((2-(1H- benzo[d]imidazol-1-yl)- 6-(3-methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 386 387 30 72

(R)-((2-(1H-benzo[d]- [1,2,3]triazol-1-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 387 388 30 73

(R)-((2-(6-fluoro-1H- indazol-4-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 404 405 25 74

(R)-((2-(3-hydroxy- phenyl)-6-(3-methyl- morpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶- sulfanone 362 363 24 75

(R)-((2′-amino-6-(3- methylmorpholino)-[2,5′- bipyrimidin]-4-yl)imino)-dimethyl-λ⁶-sulfanone 363 364 24 76

(R)-((2-(2-isopropyl-1H- benzo[d]imidazol-1-yl)- 6-(3-methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 428 429 30 77

(R)-((2-(6-aminopyridin- 3-yl)-6-(3-methyl- morpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶- sulfanone 362 363 24 78

(R)-dimethyl((6-(3- methylmorpholino)-2- (1H-pyrrolo[2,3-c]-pyridin-4-yl)pyrimidin-4- yl)imino)-λ⁶-sulfanone 386 387 25 79

(R)-((2-(1H-imidazo[4,5- c]pyridin-l-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 387 388 36 80

(R)-dimethyl((2-(6- methyl-1H-benzo[d]- imidazol-1-yl)-6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- λ⁶-sulfanone 400 401 34 81

(R)-((2-(1H-imidazol-1- yl)-6-(3-methyl- morpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶- sulfanone 336 337 30 82

(R)-dimethyl((2-(4- methyl-1H-imidazol-1- yl)-6-(3-methyl-morpholino)pyrimidin-4- yl)imino)-λ⁶-sulfanone 350 351 30 83

(R)-dimethyl((6-(3- methylmorpholino)-2-(2- (trifluoromethyl)-1H-benzo[d]imidazol-1-yl)- pyrimidin-4-yl)imino)- λ⁶-sulfanone 454 455 3484

(R)-((2-(4,5-dimethyl- 1H-imidazol-1-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)- imino)dimethyl-λ⁶- sulfanone 364 365 30 85

(R)-((2-(1H-indazol-1- yl)-6-(3-methyl- morpholino)pyrimidin-4-yl)imino)dimethyl-λ⁶- sulfanone 386 387 30 86

(R)-((2-(2-(difluoro- methyl)-1H-benzo[d]- imidazol-1-yl)-6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 436 43734 87

(R)-dimethyl((6-(3- methylmorpholino)-2-(2- (2,2,2-trifluoroethoxy)-1H-pyrrolo[2,3- b]pyridin-4-yl)pyrimidin- 4-yl)imino)-λ⁶-sulfanone 484485 25 88

(R)-((2-(6-fluoro-1H- indol-4-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 403 404 11 89

(R)-((2-(2,5-dimethyl- 1H-imidazol-1-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 364 365 30 90

(R)-dimethyl((6-(3- methylmorpholino)-2-(2- (trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7- yl)pyrimidin-4-yl)imino)- λ⁶-sulfanone 455 45634 91

(R)-((2-(2-chloro-1H- imidazol-1-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 370 371 30 92

((2-(1H-benzo[d]- imidazol-1-yl)-6-((R)-3- methylmorpholino)-pyrimidin-4-yl)imino)- (cyclopropyl)(methyl)- λ⁶-sulfanone 412 413 29 93

((2-(6-aminopyridin-3- yl)-6-((R)-3-methyl- morpholino)pyrimidin-4-yl)imino)(cyclopropyl)- (methyl)-λ⁶-sulfanone 388 389 24 94

(R)-((2-(7-fluoro-2- methyl-1H-benzo[d]- imidazol-1-yl)-6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 418 41934 95

Cyclopropyl(methyl)((2- (2-methyl-1H-benzo[d]- imidazol-1-yl)-6-((R)-3-methylmorpholino)- pyrimidin-4-yl)imino)- λ⁶-sulfanone 426 427 29 96

Methyl((2-(2-methyl-1H- benzo[d]imidazol-1-yl)- 6-((R)-3-methyl-morpholino)pyrimidin-4- yl)imino)(oxetan-3-yl)- λ⁶-sulfanone 442 443 2997

(R)-dimethyl((6-(3- methylmorpholino)-2- (pyridin-3-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone 347 348 10 98

(R)-dimethyl((6-(3- methylmorpholino)-2- (pyridin-4-yl)pyrimidin-4-yl)imino)-λ⁶-sulfanone 347 348 10 99

(R)-((2-(1H-indol-4-yl)- 6-(3-methylmorpholino)- pyrimidin-4-yl)imino)-dimethyl-λ⁶-sulfanone 385 386 11 100

Methyl((6-((R)-3- methylmorpholino)-2- (1H-pyrrolo[2,3-c]-pyridin-4-yl)pyrimidin-4- yl)imino)(oxetan-3-yl)- λ⁶-sulfanone 428 42911 101

(R)-((2-(1H-benzo[d]- imidazol-4-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 386 387 10 102

(R)-((2-(5,6-difluoro-1H- benzo[d]imidazol-1-yl)-6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 422423 29 103

(R)-dimethyl((6-(3- methylmorpholino)-2-(2- methylpyridin-4-yl)-pyrimidin-4-yl)imino)- λ⁶-sulfanone 361 362 10 104

(R)-4-(4-((dimethyl(oxo)- l6-sulfaneylidene)- amino)-6-(3-methyl-morpholino)pyrimidin-2- yl)-1H-pyrrolo[2,3-b]- pyridine-2-carbonitrile411 412 11 105

(R)-((2-(2-amino-6- cyclopropylpyridin-4-yl)- 6-(3-methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 402 403 14 106

(R)-((2-(6-fluoro-1H- benzo[d]imidazol-1-yl)- 6-(3-methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 404 405 35 107

(R)-((2-(6-fluoro-2- methyl-1H-benzo[d]- imidazol-1-yl)-6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 418 41935 108

(R)-((2-(5-fluoro-2- methyl-1H-benzo[d]- imidazol-1-yl)-6-(3-methylmorpholino)- pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 418 41935 109

(R)-((2-(5-fluoro-1H- benzo[d]imidazol-1-yl)- 6-(3-methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 404 405 35 110

(R)-((2-(1H-imidazo[4,5- c]pyridin-l-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 387 388 35 111

(R)-((2-(2-amino-6- methoxypyridin-4-yl)-6- (3-methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 392 393 17 112

(R)-6-amino-4-(4- ((dimethyl(oxo)-λ⁶- sulfaneylidene)amino)-6-(3-methylmorpholino)- pyrimidin-2-yl)-N- methylpicolinamide 419 420 50113

((2-(2-amino-6- chloropyridin-4-yl)-6- ((R)-3-methyl-morpholino)pyrimidin-4- yl)imino)(cyclopropyl)- (methyl)-λ⁶-sulfanone422 423 13 114

(R)-dimethyl((6-(3- methylmorpholino)-2- (1H-pyrazol-3-yl)-pyrimidin-4-yl)imino)- λ⁶-sulfanone 336 337 10 115

(R)-((2-(2-methoxy- pyridin-4-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 377 378 10 116

((2-(2-Amino-6- chloropyridin-4-yl)-6- ((R)-3-methyl-morpholino)pyrimidin-4- yl)imino)(methyl)- (oxetan-3-yl)-λ⁶- sulfanone438 439 13 117

(R)-((2-(2-amino-6- ethoxypyridin-4-yl)-6-(3- methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 406 407 17 118

((2-(2-Amino-6- methoxypyridin-4-yl)-6- ((R)-3-methyl-morpholino)pyrimidin-4- yl)imino)(methyl)- (oxetan-3-yl)-λ⁶- sulfanone434 435 17 119

Methyl((6-((R)-3- methylmorpholino)-2- (1H-pyrrolo[2,3-b]-pyridin-4-yl)pyrimidin-4- yl)imino)(pyridin-3-yl)- λ⁶-sulfanone 449 45016 120

Methyl(1-methyl-1H- pyrazol-4-yl)((6-((R)-3- methylmorpholino)-2-(1H-pyrrolo[2,3-b]- pyridin-4-yl)pyrimidin-4- yl)imino)-λ⁶-sulfanone 452453 16 121

(R)-1-((2-(6-chloro-1H- pyrrolo[2,3-b]pyridin-4- yl)-6-(3-methyl-morpholino)pyrimidin-4- yl)imino)tetrahydro-1H- 1λ⁶-thiophene 1-oxide446 447 19 122

(R)-((2′-amino-6-(3- methylmorpholino)-[2,4′- bipyrimidin]-4-yl)imino)dimethyl-λ⁶- sulfanone 363 364 25 123

(R)-((2-(2- hydroxypyridin-4-yl)-6- (3-methylmorpholino)-pyrimidin-4-yl)imino)- dimethyl-λ⁶-sulfanone 363 364 10 124

((2-(1H-benzo[d]- imidazol-1-yl)-6-((R)-3- methylmorpholino)-pyrimidin-4-yl)imino)- (methyl)(oxetan-3-yl)-λ⁶- sulfanone 428 429 29125

((2-(2-Amino-6- methoxypyridin-4-yl)-6- ((R)-3-methyl-morpholino)pyrimidin-4- yl)imino)(cyclopropyl)- (methyl)-λ⁶-sulfanone418 419 18

The activity of the compounds in Examples 1-125 as ATR inhibitors isillustrated in the following assay. The other compounds listed below,which have not yet been made and/or tested, are predicted to haveactivity in this assay as well.

Structure IUPAC Name

methyl 2,2,2- trifluoroethyl ({6- [(3R)-3- methylmorpholin-4-yl]-2-{1H-pyrrolo [2,3-b]pyridin-4-yl} pyrimidin-4-yl}imino)-λ⁶-sulfanone

ATR/ATRIP Enzymatic Assay

Human full-length FLAG-TEV-ATR and His6-ATRIP were co-expressed inHEK293 cells. The cell pellet (20 g) was harvested and lysed in 100 mLof lysis buffer (20 mM Tris-HCl pH 7.5 at room temperature, 137 mM NaCl,10% glycerol, 1 mM DTT, 1% (v/v) Tween-20, 0.1% (v/v) NP-40, completeprotease inhibitor cocktail tablets, phosphatase inhibitor cocktailtablets, 2 mM MgCl₂, 0.2 mM EDTA, and 1 mM ATP). After sonication andcentrifugation, the supernatant was incubated at 4° C. for 3 hours with1 mL of anti-FLAG resin (Sigma catalog #A2220) that had beenpre-equilibrated in buffer A (20 mM Tris-HCl pH 7.5 at room temperature,137 mM NaCl, 10% glycerol, 1 mM DTT, 2 mM MgCl₂, and 0.2 mM EDTA). Thesample was loaded into a column, and then washed with buffer A threetimes. Protein was subsequently eluted with 2 ml of buffer B (bufferA+200 g/ml 3×FLAG peptide).

The ability of new chemical matter to inhibit the ATR catalytic activityin this ATR/ATRIP complex was assessed using a Caliper-based assay. A 2×enzyme solution (i.e., 4 nM enzyme) was prepared using 1× KinaseReaction Buffer (25 mM HEPES pH 8, 0.0055% Brij-35, 10 mM MnCl₂, and 1mM DTT). A 2× peptide solution was then prepared consisting of 10 uMFAM-labeled RAD17 peptide (GL Biochem, catalog #524315) in 1× KinaseReaction Buffer supplemented with 2 M ATP. 10 μL of the 2× enzymesolution was transferred to an assay plate containing 60 nL of testcompound (from a 3× serial dilution) in 100% DMSO. Following a 30 minuteincubation at 28° C., 10 μL of the 2× peptide solution was thentransferred to the same assay plate. The reaction was allowed toincubate at 28° C. for 6 hours. After adding 30 μL of stop buffer (100mM HEPES pH 7.5, 0.015% Brij-35, 0.2% Coating-3 Reagent (PerkinElmer,catalog #PN760050), and 50 mM EDTA), data were collected on a Caliperinstrument. Conversion values were converted to inhibition values viathe following equation: % inhibition=(max−conversion)/(max−min)*100,whereby “max” corresponds to the DMSO control and “min” corresponds tothe low control. IC₅₀ values were calculated using the followingequation in XLFit: Y=Bottom+(Top−Bottom)/1+(IC₅₀/X){circumflex over( )}HillSlope).

pCHK1 Cellular Assay

Inhibitors of ATR kinase are effective at inhibiting the ATR-drivenphosphorylation of the downstream target Chk1 kinase at Serine 345,following the addition of 4-nitroquinoline N-oxide, a chemical used toinduce DNA damage. Cellular IC₅₀ for the inhibitors of ATR describedherein were measured in HT-29 colorectal adenocarcinoma cells. HT-29cells were routinely maintained in McCoy's 5A media (ATCC Catalog#30-2007) supplemented with 10% fetal bovine serum (Sigma Catalog#F2442) and 1× Penicillin-Streptomycin (Gibco Catalog #15140-122) usinga humidified incubator (37° C., 5% CO₂, and ambient 02). In preparationfor the CHK1 (p-Ser345) ALPHASCREEN® SUREFIRE® assay, cells wereharvested and resuspended in McCoy's 5A media supplemented with 10%fetal bovine serum and 1× Penicillin-Streptomycin. Cells were seededonto a 384-well black CELLSTAR® Tissue Culture Plate (VWR Catalog#89085-314) at a density of 13,000 cells/well in a volume of 40 μL. Themicroplate was incubated overnight (approximately 20 hours) at 37° C.with 5% CO₂ and ambient 02. Stock solutions of the test compounds wereprepared in 100% DMSO (Sigma, Catalog #D2650) and serially diluted 1:3using 100% DMSO. Compounds were additionally diluted 1:33 in culturemedium, and 10 L/well were transferred to the tissue culture plate.Following the compound addition the microplate was incubated at 37° C.for 90 minutes. 10 μL of 4-nitroquinoline N-oxide (Sigma Aldrich Catalog#N8141-1G) diluted in media (final concentration 12 uM) were added tothe tissue culture plate followed by a 120 minute incubation at 37° C.The cells were then washed with PBS and lysed using 10 μL/well SUREFIRE®Kit lysis buffer diluted to 1× in water (PerkinElmer Catalog#TGRCHK1S50K), with mixing on an orbital shaker at 500 rpm for 20 min atRT. Lysates were frozen at −20° C. overnight.

4 μL/well of lysate was then transferred from the tissue culture plateto a 384-well, white, low volume, PROXIPLATE™ (PerkinElmer Catalog#600828). 5 μL/well of the acceptor bead solution, prepared by dilutingSUREFIRE® Kit activation buffer (PerkinElmer Catalog #TGRCHK1S50K) andALPHASCREEN® Protein A acceptor beads (PerkinElmer Catalog #6760617R) inSUREFIRE® Kit reaction buffer (PerkinElmer Catalog #TGRCHK1S50K), wereadded to the lysates under subdued light and incubated at roomtemperature for 120 min. 2 uL/well of the donor bead solution, preparedby diluting ALPHASCREEN® Streptavidin donor beads (PerkinElmer Catalog#6760617R) in SUREFIRE® Kit dilution buffer (PerkinElmer Catalog#TGRCHK1S50K), were added under subdued light and incubated at roomtemperature for an addition 120 minutes. The pCHK1 ALPHASCREEN® signalwas measured using an ENVISION® plate reader (PerkinElmer). IC₅₀ valueswere calculated using a four-parameter logistic curve fit using GenedataScreener software. Percent of control for each compound concentrationwas calculated by the following formula: 100*(Compound−Min)/(Max−Mn)where “Max” is the high control, DMSO, and “Min” is the low control, 5uM ATR inhibitor.

TABLE 3 ATR/ATRIP Enzyme IC₅₀ values ATR- ATRIP pCHK1 Ex IC₅₀, nM IC₅₀(nM)  1 1 46  2 5 64  3 2 44  4 8 86  5 3 48  6 N.A. 212  7 4 77  8 N.A.167  9 N.A. 136  10 26 909  11 7 17  12 4 56  13 104 73  14 122 463  15182 335  16 3 20  17a 4 38  17b 7 61  18a 258 408  18b 71 49  19 8 131 20 67 798  21 21 311  22 77 669  23 31 1718  24 36 1986  25 22 39  2681 131  27 405 1855  28 246 575  29 10 92  30 3 47  31 1.6 14  32 25910000  33 47 1617  34 3 895  35 195 1177  36 50 4668  37 306 87  38a 0.756  38b 1.4 563  39a 48 26  39b 525 1356  40a 0.8 402  40b 0.3 30  41a15 945  41b 0.8 28  42a 31 25  42b 284 940  43a 153 44  43b 387 399  44a6 902  44b 0.4 18  45a 110 65  45b 419 431  46a 8 179  46b 1 8  47 31372  48 34 263  49 159 7586  50 486 8232  51 55 439  52 0.9 44  53 0.514  54 978 3033  55 4 61  56 2 27  57 15 202  58 15 175  59 21 183  60 441  61 3 77  62 5 89  63 4 169  64 2 68  65 20 372  66 207 198  67 3 168 68 244 1448  69 59 676  70 3 48  71 2 138  72 23 4414  73 27 2317  7473 6099  75 63 1668  76 17 408  77 135 3385  78 5 22  79 233 6070  80 6720  81 353 219  82 134 670  83 45 1569  84 158 1828  85 20 7684  86 0.428  87 316 164  88 2 58  89 435 653  90 1072 133  91 334 228  92 4 46 93 115 48  94 326 10000  95 0.9 20  96 3 57  97 208 776  98 117 252  993 99 100 3 26 101 17 158 102 10 904 103 218 1217 104 88 244 105 14 757106 3 351 107 7 339 108 2 110 109 2 341 110 143 4326 111 123 273 112 2054888 113 72 51 114 480 1113 115 307 3623 116 105 58 117 277 564 118 158136 119 17 175 120 26 250 121 24 133 122 594 6478 123 821 >10000 N.A. =not available

Anti-Tumor Effects in Mouse Xenografts

The effect of compounds 1, 39a, 30, and 18b on tumor growth was assessedin a LoVo (human colorectal) mouse xenograft model. Female CD1 nude micewere injected subcutaneously in the right flank with a suspension ofLoVo cells (1 million cells/100 ul PBS+100 ul Matrigel; cells purchasedfrom ATCC and cultured following ATCC's guideline). After implantation,tumor volume (TV) was measured weekly and mice bearing tumors withvolumes between 200-250 mm³ were randomized into treatment groups of 5to 10 mice each. Mice were dosed by oral gavage, once daily for 21 dayswith either vehicle or 1, 39a, 30, and 18b at the doses reported inTable 4. The doses were scaled to the body weights (BW) of individualanimals at a dosing volume of 10 mL/Kg. Throughout the duration of studytumor growth was assessed by caliper measurement and treatment responsewas determined by percent tumor growth inhibition (% TGI; calculated asTGI%=100−([TV_(end-treat)−TV_(start-treat)]/[TV_(end-cntrl)−TV_(tart-cntrl)];where TV_(end-treat), TV_(start-treat), TV_(end-cntrl)-andTV_(tart-cntrl) are the median tumor volumes for the compound treatedand control groups respectively at the end and at the start of thestudy. Mouse body weight was measured bi-weekly, and reported aspercentage of mean BW change from Day 1. Significant tumor growthinhibition was observed for all the compounds, as shown in Table 4, withno body weight loss.

TABLE 4 Anti-tumor effect in LoVo xenograft model in CD1 nude mice TumorGrowth Body Weight Inhibition % Change % Ex. Dose (mg/Kg) (TGI %; day21) (BW %; day 21)  1 100 96* +9.8  39a 25 59* +0.9 30 10 73* +7.3  18b10 81* +0.4 * = p < 0.05 **, two-tailed test;

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein intheir entireties. Where any inconsistencies arise, material literallydisclosed herein controls.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this disclosure, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the disclosure to adapt it to various usages andconditions.

1.-101. (canceled)
 102. A method for preparing a compound of Formula 203

wherein R¹ and R² are independently chosen from C₁₋₄alkyl,C₁₋₄haloalkyl, C₃₋₆cycloalkyl, C₃₋₆heterocycloalkyl, C₅₋₁₀aryl, and 5-10membered heteroaryl, any of which is optionally substituted with one ormore R⁵ groups, or R¹ and R², together with the sulfur to which they areboth attached, form a 4, 5, 6, or 7-membered heterocycloalkyl ring whichis optionally substituted with one or more R⁵ groups; R³ is chosen fromhydrogen, C₁₋₆alkyl, and C₁₋₆haloalkyl; R⁴ is chosen from C₅₋₁₀aryl or5-10 membered heteroaryl, either of which is optionally substituted withone or more R⁶ groups; each R⁵ is independently chosen from NR⁸R⁹,halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, C₃₋₆cycloalkyl, 3-6membered heterocycloalkyl, hydroxyalkyl, OR⁸, NR⁷C(O)R⁸, NR⁷C(O)OR⁸,NR⁷C(O)NR⁸R⁹, C(O)R⁸, C(O)OR⁸, and C(O)NR⁸R⁹; each R⁶ is independentlychosen from NR¹¹R¹², halogen, cyano, hydroxy, oxo, alkyl, haloalkyl,C₃₋₆cycloalkyl, 3-6 membered heterocycloalkyl, hydroxyalkyl, OR¹¹,NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹, C(O)OR¹¹, andC(O)NR¹¹R¹²; each R⁷, R⁸ and R⁹ is independently chosen from hydrogen,C₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl, any ofwhich is optionally substituted with halo, hydroxy, C₁₋₃alkyl,C₁₋₃haloalkyl and C₁₋₃alkoxy; or any two of R⁷, R⁸ and R⁹, together withthe atom to which they are both attached can form a 3-7 memberedcycloalkyl or heterocycloalkyl ring; and each R¹⁰, R¹¹ and R¹² isindependently chosen from hydrogen, C₁₋₄alkyl, C₃₋₆cycloalkyl, 3-6membered heterocycloalkyl, any of which is optionally substituted withone or more groups chosen from halo, hydroxy and alkoxy; or any two ofR¹⁰, R¹¹ and R¹², together with the atom to which they are bothattached, can form a 3-7 membered cycloalkyl or heterocycloalkyl ring,said method comprising reacting a compound of formula 202

with a compound of formula

to yield a compound of formula
 203. 103. The method of claim 102,wherein said reacting occurs in the presence of PdCl₂(dppf).
 104. Themethod of claim 103, wherein said reacting occurs in the presence ofNa₂CO₃.
 105. The method of claim 103, wherein said reacting occurs inthe presence of dioxane.
 106. The method of claim 103, wherein saidreacting occurs in the presence of water.
 107. The method of claim 102,wherein the compound of formula 203 comprises a mixture ofdiastereomers.
 108. The method of claim 107, further comprisingseparating the mixture of diastereomers.
 109. The method of claim 102,wherein R³ is chosen from methyl, fluoromethyl, difluoromethyl, andtrifluoromethyl.
 110. The method of claim 102, wherein R⁴ is 5-10membered heteroaryl and is optionally substituted with one or more R⁶groups.
 111. The method of claim 110, wherein R⁴ is chosen from1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl,1H-imidazol-2-yl, 1H-imidazol-4-yl, pyridin-3-yl, pyridin-4-yl,pyrimidin-4-yl, 1H-indol-1-yl, 1H-indol-4-yl, 1H-indazol-1-yl,1H-indazol-4-yl, 1H-benzo[d]imidazol-1-yl, 1H-benzo[d]imidazol-4-yl,1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl,pyrazolo[1,5-a]pyridin-3-yl, imidazo[1,2-a]pyridin-3-yl,imidazo[1,2-a]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-1-yl,7H-pyrrolo[2,3-d]pyrimidin-4-yl, 1H-pyrazolo[3,4-b]pyridin-4-yl,3H-imidazo[4,5-b]pyridin-7-yl, and 1H-benzo[d][1,2,3]triazol-1-yl, anyof which is optionally substituted with one or two R⁶ groups.
 112. Themethod of claim 111, wherein R⁴ is pyridine and is optionallysubstituted with one or more R⁶ groups.
 113. The method of claim 102,wherein: each R⁶ is independently chosen from NR¹¹R¹², halogen, cyano,hydroxy, oxo, OR¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)OR¹¹, NR¹⁰C(O)NR¹¹R¹², C(O)R¹¹,C(O)OR¹¹, and C(O)NR¹¹R¹²; each R⁵ is independently chosen from C(O)R⁸,C(O)OR⁸, and C(O)NR⁸R⁹; R¹ and R² are independently chosen fromC₁₋₄alkyl, C₃₋₆cycloalkyl, and 3-6 membered heterocycloalkyl; and R⁴ ischosen from pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl,pyrrolo[2,3-c]pyridin-4-yl, benzo[d]imidazol-1-yl, any of which isoptionally substituted with one or two R⁶ groups.
 114. The method ofclaim 113, wherein each R⁶ is independently selected from NR¹¹R¹²,halogen, cyano, hydroxy, and oxo.
 115. The method of claim 114, whereinR¹ and R² are independently chosen from methyl, cyclopropyl, andoxetan-3-yl.
 116. The method of claim 115, wherein R⁴ is pyridine and isoptionally substituted with one or more R⁶ groups.
 117. The method ofclaim 116, wherein R⁴ is pyridine and is substituted with one R⁶ group.118. A product of the method of claim
 102. 119. A method for preparing acompound of Formula 205

said method comprising reacting a compound of formula 204

with a compound of formula

to yield a compound of formula
 205. 120. The method of claim 119,wherein said reacting occurs in the presence of PdCl₂(dppf).
 121. Themethod of claim 120, wherein said reacting occurs in the presence ofNa₂CO₃.
 122. The method of claim 120, wherein said reacting occurs inthe presence of dioxane.
 123. The method of claim 120, wherein saidreacting occurs in the presence of water.
 124. The method of claim 120,further comprising separating the mixture of diastereomers.
 125. Themethod of claim 124, wherein the step of separating the mixture ofdiastereomers is accomplished with chiral supercritical fluidchromatography (SFC).
 126. A product of the method of claim 119.